Role of STATs in the organism
\r\n\tThe fundamental research areas of Evolutionary Psychology can be divided into two broad categories: on the one hand, the basic cognitive processes, and the way they evolved within the species, and on the other, the adaptive social behaviors that derive from the theory of evolution itself: survival, mating, parenting, family and kinship, interactions with non-parents and cultural evolution. Indeed, Evolutionary Psychology explains at individual and group level the fundamental behaviors of social life, such as altruism, cooperation, competition, social exclusion, social support, etc. etc. Similar to the mechanisms of natural selection for physical characteristics, not only the mind follows biological laws, but also psychological abilities - such as the theory of mind, the ability to represent the intentions, thoughts, beliefs, and emotions of others - have had to adapt and must make themselves functional to the social life of individuals and groups. In addition, Sociology takes the same aspects into consideration, emphasizing the interaction, symbolic and otherwise, of individuals. The latter investigates the neural mechanisms underlying the same social behaviors that are of interest to evolutionary psychology. To study the neural correlates involved in such behaviors is necessary to understand the biological laws that underlie human behavior and brain functioning.
\r\n\r\n\tThis book aims to open a debate full of theoretical and experimental contributions among the different disciplines in social research, psychology, neuroscience, sociology, useful to give an innovative vision to the present research and future perspective on the topic.
",isbn:"978-1-83968-871-3",printIsbn:"978-1-83968-870-6",pdfIsbn:"978-1-83968-872-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"bd4df54e3fb185306ec3899db7044efb",bookSignature:"Dr. Rosalba Morese, Dr. Vincenzo Auriemma and Dr. Sara Palermo",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10450.jpg",keywords:"Evolutionary Psychology, Human Social Evolution, Human Social Behaviour, Social Cognition, Social Neuroscience, Functional Neuroimaging, Neuropsychology, Altruism, Cooperation, Social Exclusion, Social Support, Social Inclusion",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 18th 2020",dateEndSecondStepPublish:"December 21st 2020",dateEndThirdStepPublish:"February 24th 2021",dateEndFourthStepPublish:"May 15th 2021",dateEndFifthStepPublish:"July 14th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Rosalba Morese is carrying out research in the framework of Neuroscience and Social Psychology. She currently works at the Institute of Public Health of Faculty of Biomedical Sciences and at the Faculty of Communication, Culture, and Society of Università Della Svizzera Italiana, Lugano, Switzerland.",coeditorOneBiosketch:"Dr. Vincenzo Auriemma's focus is on the study of empathy in human interactions. He studied at the University of Essex in England, the University of Pisa, Genoa, Rome in Italy, and the University of Italian Switzerland in Switzerland. He is the principal responsible for the 'PERSEO' research which analyzes the reasons for the 'drop-out' in psychology.",coeditorTwoBiosketch:"Researcher of the EUROPEAN INNOVATION PARTNERSHIP on Active and Healthy Ageing and Assistant Specialty Chief Editor for Frontiers in Psychology - Neuropsychology.",coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"214435",title:"Dr.",name:"Rosalba",middleName:null,surname:"Morese",slug:"rosalba-morese",fullName:"Rosalba Morese",profilePictureURL:"https://mts.intechopen.com/storage/users/214435/images/system/214435.jpg",biography:"Rosalba Morese obtained a degree in psychology at the University of Parma. She subsequently held various\nteaching positions at the Department of Psychology and the Faculty of Medicine and Surgery of the\nUniversity of Parma.\nHer training continued with the attainment of the title of PhD in Neuroscience at the University of Turin,\nduring which she acquired and developed interdisciplinary skills and point of view through the application\nof bioimaging and psychophysiological methods to investigate the neurophysiological mechanisms involved\nduring communication and social interactions.",institutionString:"Universita della Svizzera Italiana",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"Universita della Svizzera Italiana",institutionURL:null,country:{name:"Switzerland"}}}],coeditorOne:{id:"338363",title:"Dr.",name:"Vincenzo",middleName:null,surname:"Auriemma",slug:"vincenzo-auriemma",fullName:"Vincenzo Auriemma",profilePictureURL:"https://mts.intechopen.com/storage/users/no_image.jpg",biography:'He is pursuing a PhD in Sociology from the University of Salerno, Italy. He is a researcher of sociology and neurosociology at the University of Salerno, Italy. His focus is on the study of empathy in human interactions and he studied at the University of Essex in England, the University of Pisa, Genoa, Rome 3 in Italy and the University of Italian Switzerland in Switzerland. He has participated in national and international conferences with about 25 reports/communications. He is the principal responsible for the "PERSEO" research which analyzes the reasons for the "drop-out" in psychology, using the methodology of the Gounded Theory and analyzing empathy, fear and panic. He is Co-Editor for Frontiers. He is also a member of the Italian Society of Sociology (AIS).',institutionString:"University of Salerno",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Salerno",institutionURL:null,country:{name:"Italy"}}},coeditorTwo:{id:"233998",title:"Ph.D.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo",profilePictureURL:"https://mts.intechopen.com/storage/users/233998/images/system/233998.jpeg",biography:"Sara Palermo is a MSc in Clinical Psychology and a PhD in Experimental Neuroscience. Moreover, she obtained the National Scientific Enabling Certificate for Associate Professorship in April 2017 (ASN-2017). She is an expert in experimental neuroscience, clinical neuropsychology and advance neuropsychological testing. Moreover, she performs multidimensional geriatric evaluation and basic neurological symptomatology detection in patients with neurodegenerative disorders. She is also engaged in Activation Likelihood Estimation meta-analysis of neuroimaging studies.\r\nShe worked as a postdoc research fellow at the Department of Neuroscience 'Rita Levi Montalcini” in Turin until July 2017. Since then she works as research fellow at the Department of Psychology in Turin. To date, she owns three research Group memberships at the University of Turin (Italy). She is a member of the 'Center for the Study of Movement Disorders” (research area: Neurology) and the 'Placebo Responses Mapping Group” (research area: Physiology) at the Department of Neuroscience, and a member of the 'Neuropsychology of cognitive impairment and central nervous system degenerative diseases Group” at the Department of Psychology (Research Area: Psychobiology and physiological psychology).\r\nThe main topics of her research are the study of awareness of illness, metacognitive-executive deficits in neuropsychiatric and neurological disorders, physical and cognitive frailty in the elderly, and placebo/nocebo phenomena. Interestingly, all of them may represent appealing perspectives from which to study how neuropsychological abnormalities can be explained in terms of brain activities and with the use of neuropsychiatric and neuropsychological batteries considering a neurocognitive approach. Given her research interests and scientific publications, she has been an ordinary member of the Italian Society of Neuropsychology (SINP), of the Italian Association of Psychogeriatrics (AIP), of the Italian Society of Neurology for Dementia (SiNdem), and – finally – of the international Society for Interdisciplinary Placebo Studies (SIPS). Importantly, she is a member of the European Innovation Partnership on Active and Healthy Aging (EIP on AHA), for which she is involved in the Action Group A3 Functional decline and frailty. \r\n\r\nSara Palermo is Panel Editor for 'EC Psychology and Psychiatry'. She was recently appointed as Specialty Chief Editor for 'Frontiers in Psychology - Neuropsychology'.",institutionString:"University of Turin",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"3",institution:{name:"University of Turin",institutionURL:null,country:{name:"Italy"}}},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"21",title:"Psychology",slug:"psychology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"259492",firstName:"Sara",lastName:"Gojević-Zrnić",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/259492/images/7469_n.png",email:"sara.p@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"5810",title:"Socialization",subtitle:"A Multidimensional Perspective",isOpenForSubmission:!1,hash:"bfac2e9c0ec2963193e9d15d617c6a01",slug:"socialization-a-multidimensional-perspective",bookSignature:"Rosalba Morese, Sara Palermo and Juri Nervo",coverURL:"https://cdn.intechopen.com/books/images_new/5810.jpg",editedByType:"Edited by",editors:[{id:"214435",title:"Dr.",name:"Rosalba",surname:"Morese",slug:"rosalba-morese",fullName:"Rosalba Morese"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7818",title:"Social Isolation",subtitle:"An Interdisciplinary View",isOpenForSubmission:!1,hash:"db3b513d7d35476f333a0d4a3147935b",slug:"social-isolation-an-interdisciplinary-view",bookSignature:"Rosalba Morese, Sara Palermo and Raffaella Fiorella",coverURL:"https://cdn.intechopen.com/books/images_new/7818.jpg",editedByType:"Edited by",editors:[{id:"214435",title:"Dr.",name:"Rosalba",surname:"Morese",slug:"rosalba-morese",fullName:"Rosalba Morese"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8262",title:"The New Forms of Social Exclusion",subtitle:null,isOpenForSubmission:!1,hash:"29bf235aa7659d3651183fe9ea49dc0d",slug:"the-new-forms-of-social-exclusion",bookSignature:"Rosalba Morese and Sara Palermo",coverURL:"https://cdn.intechopen.com/books/images_new/8262.jpg",editedByType:"Edited by",editors:[{id:"214435",title:"Dr.",name:"Rosalba",surname:"Morese",slug:"rosalba-morese",fullName:"Rosalba Morese"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6494",title:"Behavior Analysis",subtitle:null,isOpenForSubmission:!1,hash:"72a81a7163705b2765f9eb0b21dec70e",slug:"behavior-analysis",bookSignature:"Huei-Tse Hou and Carolyn S. 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Since then, a number of cytokines have been recognized to activate various STAT proteins. STATs constitute a family of seven transcription factors, STAT1α/β, STAT2, STAT3α/β, STAT4, STAT5A, STAT5B and STAT6, that transduce signals from a variety of extracellular stimuli initiated by different cytokine families that aside from interferons (interferon α, β and γ) include gp130 cytokines, i.e., IL-6, IL-12, IL-23 and γC cytokines that include IL-2, IL-15 and IL-21 [1 ].
Although structurally similar, the seven STAT family members possess diverse biological roles and are engaged in numerous processes from embryonic development, organogenesis, cell differentiation to regulation of immune processes. Awareness of their important role in regulation of cell proliferation, differentiation and survival has spurred interest in investigation of their activity in malignant transformation [2]. Evidence has now accumulated that confirms their role in pathogenesis of leukemias and numerous solid tumors [3] (Table1).
Aside from cytokine receptors, STATs are also activated by receptors for growth factors (family of tyrosine kinase receptors) that include receptors for epidermal growth factor - EGFR, platelet-derived growth factor - PDGF, hepatocyte growth factor - HGF and colony-stimulating factor 1- CSF-1 receptors that possess an intrinsic tyrosine kinase activity [4]. These receptors may activate STAT proteins either directly or indirectly by means of JAK kinase proteins. Also, free intracellular enzymes, i.e., non-receptor tyrosine kinases that include oncogenes src and bcr-abl activate various STATs [5].
Different biological processes regulated by STAT proteins | ||||
Embryonic development | ||||
Organogenesis and function | ||||
Cells proliferation | ||||
Cell differentiation, growth and apoptosis | ||||
Innate and adoptive immunity | ||||
Inflammation | ||||
Angiogenesis | ||||
Wound healing | ||||
Malignant transformation |
Role of STATs in the organism
Interaction of cytokines and their specific receptors directly activates free intracellular non-receptor enzymes, Janus kinases, and subsequently, latent STAT transcription factors that through the JAK/STAT signaling pathway lead to the expression of numerous genes that regulate important cellular processes. It is of importance that numerous cytokines, growth factors in different cell types activate STAT1, STAT3 and STAT5 and mediate broadly diverse biologic processes that control cell homeostasis. On the other hand, STATs such as STAT4 and STAT6 have a more specific role and they are engaged in T helper cell differentiation and maintenance of equilibrium between Th1 and Th2 immune response [6]. Defects in STAT molecules can lead to serious defects in development and to fetal death indicating the importance of JAK/STAT pathway in normal cell development. Defects in the JAK/STAT signaling pathway are often encountered in primary malignant tumors, as well as in peripheral blood lymphocytes [7,8,9] and STAT3 has been the first to be identified as a potential oncogene [2] (Fig.1).
Given the critical roles of STAT proteins such as activation of pro-inflammatory and anti-proliferative processes by STAT1 and control of cell-cycle progression and apoptosis by STAT3 and STAT5 it has been established in many studies that their dysregulation can contribute to oncogenesis [10] by increasing proliferation and slowing-down apoptosis. In this sense, studies show that STAT3 is activated in a majority of breast and prostate cancers, and that STAT3 inhibition using RNA interference or a dominant negative genotype leads to reduced cell proliferation, survival, and induces wound healing. Further, blocking STAT3 interaction with EGFR using peptide aptamers has been shown to reduce tumor growth. On the other hand, STAT1 has been primarily defined as a tumor suppressor gene and its inactivation was associated with malignant transformation. Initially STAT proteins were extensively studied in leukemias, but later their role in the development of different solid tumors has been shown.
Mechanisms of STAT signaling upon activation of different tyrosine kinase (TK) signaling pathways that can induce activation of STAT proteins. In the case of growth factors like EGF that bind to receptor tyrosine kinases (RTKs), the receptor can directly phosphorylate STATs and/or indirectly induce STAT phosphorylation. Also, cytokines, like IL-6, that bind to cytokine receptors lacking intrinsic TK activity undergo ligand-induced dimerization of the receptor that results in phosphorylation of receptor-associated JAK kinases. JAKs in turn phosphorylate the receptor cytoplasmic tails on tyrosine, providing “docking sites” for recruitment of monomeric STATs. JAKs then phosphorylate the recruited STAT proteins on tyrosine, inducing dimerization, nuclear translocation, and DNA-binding activity. Other non-receptor bound free intracellular enzymes named non-receptor TKs such as SRC family kinases are also involved and can directly induce STAT activation. Once in the nucleus, activated STAT proteins bind to specific DNA sequences in the promoters of genes and induce their expression. In the context of oncogenesis, constitutive activation of TK-STAT signaling pathways induces elevated expression of genes involved in controlling cellular processes such as cell proliferation and survival.
Aside from their role in the development of tumors STAT1,3 and 5 can be considered as molecular markers for early detection of certain types of tumors, as well as prognostic factors for determining tumor aggressiveness and predictors of response to various types of therapy. Novel data also indicate functional interplay between several activated STATs and association of STAT5 with certain well differentiated tumors with favorable prognosis [11].Based on numerous new data it appears that dysregulation of STAT signaling pathway may serve as a basis for designing novel targeted molecular therapeutic strategies that hold great potential for the treatment of solid tumors and leukemias.
STATs share structurally and functionally conserved domains that include the amino-terminal domain (NH2), the coiled-coiled domain (CCD), the DNA binding domain (DBD), the linker domain and the SH2/tyrosine activation domain [12]. In contrast, the carboxyl-terminal transcriptional activation domain (TAD) is quite divergent and contributes to STAT specificity (Table 2).
Functionally, the amino-terminal domain of STAT molecules is the oligomerization domain that interacts with other proteins and mediates oligomerization of STAT dimers to form tetramers [13]. The DNA binding domain defines the DNA-binding specificity to tandem GAS elements and each STAT component of the dimer recognizes bases in the most proximal half of GAS and mediates distinct signals for specific ligands.
SH2 domain, located near the C-terminal domain, plays an important role in signaling through its capacity to bind to specific phosphotyrosine motifs and to mediate specific interactions. Consistent with this, it is the most highly conserved STAT domain. The ability of this SH2 domain to recognize specific phosphotyrosine motifs plays an essential role in three STAT signaling events that include recruitment to the phosphorylated cytokine receptor through recognition of specific receptor phosphotyrosine motifs, association with the activating JAKs, as well as STAT homo- or heterodimerization [14].
Domain | Role |
NH2-terminal domain Oligomerization domain | Interacts with other proteins and mediates oligomerization of STAT dimers to form tetramers |
DNA binding domain | Defines the DNA-binding specificity and mediates distinct signals for specific ligands |
SH2 domain | Mediates specific interactions between STAT and receptors, STAT and JAK and STAT homo or hetero dimerization |
COOH-terminal domain Transcription activation domain (TAD) | TAD regulates the transcriptional activity of STATs and provides specificity |
Tyrosine residue | Phosphorylation site in the COOH-terminal domain that regulates the DNA-binding activity of all STATs. On phosphorylation mediates STAT dimerization |
Serine residue | A second phosphorylation site in the C-terminal domain |
STAT structure
Close to the SH2 domain the critical tyrosine residue is located that is required for SH-phosphotyrosine interaction and thus STAT activation. This tyrosine residue is then rapidly phosphorylated by the active JAK determining STAT dimerization by binding to the SH2 domain of the reciprocal STAT molecule.
A conserved serine residue in the C-terminal domain of STAT1,3, and 5 is a second phosphorylation site that enhances DNA binding affinity and transcriptional activity [15]. It has been determined that the transcriptional activity of several STATs can be modulated through serine phosphorylation. Serine phosphorylation appears to enhance the transcription of some, but not all target genes. It has been suggested that serine phosphorylation may alter the affinity for other transcriptional regulators like minichromosome maintenance complex component 5 (MCM5) and BRCA1 [12].
C-terminal domain also encodes transcriptional activation domain (TAD) that contributes to STAT specificity and is thought to be involved in communication with transcriptional complexes, to regulate the transcriptional activity of STATs and provide functional specificity. Altered serine phosphorylation site associated with the c-terminal transactivation domain truncation of STAT1 and STAT3 reduces their transcriptional capacity by 20% [16]. Moreover, a c-TAD truncation leads to the α and β isoforms of STAT proteins that are biologically significant and appear to affect the cell’s fate [13].
When ligands bind to their receptors they initiate a cascade of intracellular phosphorylation events. However, members of the hematopoietin receptor family possess no catalytic kinase activity. Rather, they rely on members of the JAK family of tyrosine kinases to provide this activity. JAKs are constitutively associated with a proline-rich domain of these receptors [17]. Upon ligand stimulation, receptors undergo the conformational changes that bring JAKs into proximity of each other, enabling activation by trans-phosphorylation [18]. Once activated, JAKs mediate the described signal transduction. Several studies have also suggested that JAKs associate with the receptor tyrosine kinases [12]. The phosphorylated JAKs, in turn, mediate phosphorylation at the specific receptor tyrosine residues, which then serve as docking sites for STATs and other signaling molecules. Once recruited to the receptor, STATs also become phosphorylated by JAKs, on a single tyrosine residue. The position of these tyrosines in STAT molecule is specific for each member of STAT family of proteins, such as Tyr 701 for STAT1, Tyr690 for STAT2, Tyr 705 for STAT3, Tyr 693 for STAT4, Tyr 694 for STAT5, and Tyr 641 for STAT6. Their phosphorylation mediates STAT dimerization which occurs by binding of the SH2 domain of one molecule with the domain containing the phosphotyrosine of another STAT molecule [19], so the resulting dimers are thus stabilized by bivalent bonds. STAT2 is the only STAT representative that does not act as a homodimer, forming instead a complex with STAT1 and p48. As a response to several cytokines, the heterodimers STAT1-2, STAT1-3 STAT5A-5B are formed, while no heterodimers with STAT 4 and STAT6 have been identified [20] (Table 3).
Activated STATs dissociate from the receptor, dimerize, translocate to the nucleus and bind to members of the GAS (gamma activated site) family of enhancers. There are several more recent developments regarding STAT signaling, structural studies, nuclear as well as mitochondrial translocation, gene targeting and newly identified regulatory molecules.
Classical activation of STATs occurs after cytokine binding to cell-surface receptors that initiates a cascade of intracellular phosphorylation events. The phosphorylation of STATs is essential not only for dimerization, but also for the concomitant translocation of the dimers into the nucleus. Binding of STAT1 and STAT5B to importin-α5, a part of the nucleocytoplasmic transport machinery, has been described [21].
Considering that a second phosphorylation site is serine residue in the c-terminal domain, STATs, in addition to tyrosine phosphorylation can be serine phosphorylated by various serine kinases [22] that regulate and increase STAT1,3 and 5 transcriptional activity. It is of interest that one of the kinases responsible for the phosphorylation of this serine in STAT1 and STAT3, belongs to the MAP kinases family (ERKs, JNK and p38) which emphasizes the important ‘‘cross-talk’’ occurring between the two transductional pathways [23]. Furthermore, there is also evidence of the activity of ERK-independent serine kinases [24], such as the role of protein kinase C (PKC) in serine phosphorylation of STATs [25] and mTOR of the PKI2 pathway. The relative contribution of each of these serine kinases to STAT signaling in vivo would depend on cell-type specific expression of kinases [22]. Therefore, STATs can be phosphorylated in great many serine/threonine residues, which may modulate DNA binding and/or their transcriptional activity [26].
One can envision a negative feedback mechanism in which serine phosphorylation of STATs promotes the induction of physiologic inhibitors of STAT signaling, such as those of the suppressor of cytokine signaling (SOCS) family that inhibit at the level of JAKs [27]. Assumingly dual functional role is thus implied for STAT serine phosphorylation events, whereby the same serine kinases can apparently both enhance and repress STAT signaling, the indirect negative effect being due to preferential association of STAT proteins with the serine kinases, precluding interaction with tyrosine kinases [2, 25].
In addition to classical, canonical activation by tyrosine phosphorylation, the noncanonical STAT activation includes, besides serine phosphorylation, other, phosphorylation-independent modifications that regulate their activity. In this sense, it has been shown that following stimulation of cells with IL-1 plus IL-6 unphosphorylated STAT3 affects gene expression in the nucleus through binding to NF-κB that mediates its nuclear import [28]. Furthermore, the classical IL-6 mediated activation of STAT3 induces tyrosine-phosphorylation of STAT3 and activates many genes, including the STAT3 gene itself that results in STAT3 synthesis that in its unphosphorylated form can induce not only the synthesis of IL-6 but also the expression of other genes such as RANTES, IL-8, Met, and MRAS.
Aside from this, the noncanonical STAT activation includes acetylation of lysine 685 in the SH2 STAT domain [29] that occurs in IL-6-induced acute phase reactions [30]. Novel findings indicate that acetylation of STAT3 is an important regulatory modification that influences protein–protein interaction and its transcriptional activity. Moreover, in oncogenesis new data regarding transmembrane glycoprotein CD44 [31], a marker of tumor metastatic phenotype, translocates into the nucleus in association with acetylated STAT3 and by regulating transcription of cyclin D enhances cell proliferation [32] (Fig. 2).
Also, many more posttranslational STAT modifications such as isgylation [33], sumoylation [34] and ubiquitination [35] are being explored in STAT-dependent tumor formation and metastasis. These noncanonical pathways include the many roles of nontyrosine phosphorylated STATs, which alter their stability, dimerization, nuclear localization, transcriptional activation function, and association with histone acetyltransferases (HAT), and histone deacetylases (HDAC) [36] (Fig. 2).
Different signaling pathways initiated by phosphorylation of STAT3 on tyrosine or serine residues. STAT3 is constitutively imported into and exported from the nucleus independent of its phosphorylation status. Oncogenic Ras can stimulate the autocrine production of IL-6, and the resulting phosphorylation of STAT3 Tyr705 promotes dimerization and the ability to bind specific DNA target sequences. STAT3 can also be phosphorylated on Ser727 and can mediate nuclear import of the NF-κB transcription factor. Serine phosphorylated STAT3 stimulates the electron transport chain in mitochondria and augments transformation by oncogenic Ras.
The duration of STATs activation is a temporary process, thus within hours the activating signals decay and the STATs are exported back to the cytoplasm. Negative nuclear regulators of STATs are nuclear tyrosine phosphatases that induce STAT dephosphorylation in the nucleus important for its export back to the cytoplasm. There is evidence that a specific nuclear tyrosine phosphatase (TC45), is a phosphatase relevant for STAT1 and STAT3 [37]. In addition, it has been reported that cells lacking this enzyme retain tyrosine phosphorylated STAT1 for much longer than normal cells, and overexpression of TC45 leads to dephosphorylation of STAT5 [38]. However, TC45 has also been implicated in regulating cytoplasmic dephosphorylation of JAK1 and JAK3 [39].
Recently, the negative activity on STAT protein of a group of nuclear proteins termed “proteins that inhibit activated STATs” (PIAS) has been discovered. Studies in cultured mammalian cells indicated that PIAS1 and PIAS3 interact only with tyrosine-phosphorylated STAT1 and STAT3, respectively [40]. PIAS prevents their binding to DNA, especially of STAT1, or it speeds-up their degradation in the proteasome.
Besides nuclear, other phosphatases in the cytoplasm also represent negative STAT regulators, they include phosphatases such as SH2-containing phosphatase-1 (SH1), SH2, and protein-tyrosine-phosphatase-1B (PTP1B) implicated as cytoplasmic regulators of JAKs or STATs’ phosphorylation [38].
The activity of STAT proteins is also regulated by the inhibitors of the suppressors of the cytokine signal (SOCS) family, responsible for modulating the JAK-STAT pathway by acting on the JAK kinases. These cytokine-induced SOCS proteins are recruited to active receptor complexes to cause inhibition, and can also cause protein turnover of the receptor through a process of proteolytic degradation ubiquitine-proteasome mediated [41]. As SOCS belong to the family of target STAT genes they constitute with them a classical negative feedback mechanism [12] that can negatively regulate their own phosphorylation state [42]. Several members of this family have been identified, SOCS1,2,3,4,5,6 and 7. These regulatory proteins have an indirect negative effect on STATs by inhibiting their activating enzymes, especially Janus kinases (JAK1, JAK2, JAK3 and Tyk2), as well as, upstream receptors for growth factors [43]. Considering their negative regulatory role, SOCS proteins represent an important intracellular mechanism for limiting the potentially adverse effects of cytokines in immune reactions [44].
Aside from these mechanisms, mutations that augment the function of their activators or decreases the function of their inhibitors may lead to STAT hyperactivity and their engagement in malignant transformation.
Moreover, due to alternate splicing of STAT gene the short forms of STATs, i.e., inactive STATβ form, can potentially act as dominant-negative protein and by competitive inhibition occupy DNA as non-functional protein without transcriptional capability or by binding to wild-type STATs form [45] competitive inhibition, prevent binding of the STATα isoform and transcription of target genes. Aside from that, the truncated STATγ isoform of this molecule that is created by proteolysis, also competitively inhibits transcription mediated by the active α form (Table 3).
Positive regulation of STATs | Effects | ||||||||||
Canonical regulation of STATs | |||||||||||
STAT1 - Tyr 701 | STAT4 - Tyr 693 | ||||||||||
Phosphorylation of tyrosine | STAT2 - Tyr690 | STAT5 - Tyr 694 | |||||||||
STAT3 - Tyr 705 | STAT6 - Tyr 641 | ||||||||||
Noncannonical regulation of STATs | |||||||||||
STAT3 - Ser727 | |||||||||||
Phosphorylation of serine | STAT4 - Ser721 | ||||||||||
STAT5 - Ser725/730 | |||||||||||
Unphosphorylated STAT | IL-6 gene dependant expression IL-6 mediated acute phase reactions | ||||||||||
NFκB | Nuclear import of CD44 | ||||||||||
Acetylation | |||||||||||
Isgylation | |||||||||||
Sumoylation | |||||||||||
Genetic regulation | |||||||||||
Mutations | |||||||||||
Hypermorphic allele of STAT3 | Increased transcription | ||||||||||
Epigenetic regulation | |||||||||||
Histone acetyl transferase (HAT) | |||||||||||
Negative regulation of STATs | |||||||||||
Negative cytoplasmic regulators | |||||||||||
Tyrosine phosphatase (SHP1,2) | Dephosphorylation | ||||||||||
Protein-tyrosine-phosphatase-1B | |||||||||||
Suppressors of cytokine signals (SOCS1-7) | Inhibit JAK degrade receptors | ||||||||||
Proteases | STAT inactive forms (β and γ) | ||||||||||
Negative nuclear regulators | |||||||||||
Nuclear tyrosine phosphatase | Dephosphorylation | ||||||||||
Proteins that inhibit activated STATs (PIAS1-3) | Inhibits STAT1-3 DNA binding Proteasome degradation | ||||||||||
DNA methyltransferase (DNMT) | Decreased transcription | ||||||||||
Ubiquitination | Degradation |
Regulation of STAT activity
Aside from their essential role in mediating the effect of cytokines, it has been shown that STATs can have a significant role in tumor development and they are being considered as potential oncogenes. In normal cells, the activation of STAT proteins is transient, ranging from between a few minutes to a few hours. However, in a large group of different tumors constitutive activation of STAT family, especially STAT3 and STAT5 members, as well as the loss of STAT1 signaling, has been detected [3, 46]. Novel results indicate that STAT proteins regulate numerous pathways that participate in oncogenesis, such as cell cycle progression, apoptosis, angiogenesis, tumor invasiveness, metastasis, and immune response evasion. Based on this STAT proteins have become significant target molecules in novel therapeutic approaches in oncology as blocking of these molecules, directly or indirectly, may arrest the malignant process [47].
Gough et al. [48] provide evidence that STAT3 has joined a set of transcription factors that in mitochondria exhibit noncanonical roles independent of classical STAT3-mediated transcription in the nucleus. In this sense, mitochondria have become important in cancer research because they regulate proapoptotic and antiapoptotic factors.
It is also of importance that according to their general principle of action STAT proteins may be divided into two groups that differ greatly. The group that comprises STAT2, STAT4 and STAT6 is activated by a limited number of cytokines and it is engaged in T cell development and the effect of interferons, while the other group that is comprised of STAT1, STAT3 and STAT5 is activated in numerous tissues and cell types by great many cytokines, different hormones and growth factors and aside from mediating immune reactions, regulates many important general processes such as cell proliferation, differentiation and survival in embryogenesis, as well as breast development [49]. In that sense, this second group of STAT proteins is of importance in malignant transformation. Aside from that, earlier results indicated that active STAT1 protein has tumor-suppressor characteristics as it down-regulates cell proliferation and induces apoptosis, so that its decreased activity is associated with numerous neoplasias. On the other hand, it has been shown for STAT3 and STAT5 that they are proto-oncogenes that activate oncogenes, c-myc, cyklin D and antiapoptotic Bcl-xL protein, facilitate passage through G1/S check-point and in that sense, aside from down-regulating apoptosis, enhance cell proliferation and transformation [12].
It has been shown that STAT3 is frequently activated in hematological and epithelial malignancies. Constitutive activation of STAT3 leads to proliferation of tumor cells and prevents apoptosis, down-regulates the production of numerous proinflamatory cytokines and chemokines and leads to secretion of factors that prevent dendritic cell (DC) maturation that suppresses adaptive antitumor immunity establishment. Aside from the disturbance of the JAK/STAT signaling pathway in primary tumors, a similar finding is frequently found in peripheral blood lymphocytes of patients with malignancies [3].
It is known that invasive tumors need to modulate gene expression in a manner that impairs the activity of innate and adaptive immunity in immune surveillance [50, 51]. STAT3 positive tumors achieve this by preventing the production of proinflamatory cytokines, i.e., “danger signals”. Activation of the transcription factor STAT3 in the tumor and adjacent immune cells, including tumor associated macrophages (TAMs),T regulatory cells (Treg cells), DCs, Th1 cells, Th2 cells, B regulatory cells (Bregs), myeloid derived suppressor cells (MDSCs), Th17 cells, as well as, normal epithelial cells, lead to production of cytokines IL-1β, IL-6, IL-10, IL-17, as well as VEGF creating a feedback loop that promotes tumor growth, angiogenesis, evasion of immune surveillance and metastasis [52].
It has been shown that especially tumor produced IL-6 through JAKs/STAT3 signaling has an important role in modulating the tumor-associated immune microenvironment. IL-6 has pleiotropic functions by activating numerous cell types expressing membrane-bound gp130 IL-6 receptor, i.e., classical IL-6 signaling, as well as, by soluble form of the IL-6 receptor (sIL-6 receptor) that after binding IL-6 and interaction with gp130 in the form of IL-6 trans-signaling modulates a broad spectrum of target cells including epithelial cells, neutrophils, macrophages, and T cells [53]. Upregulated STAT3 in TAM has been shown to enhance the expression of IL-23 that leads to the expansion of Tregs, while conversely, transcriptionally repressing IL-12 that supports proinflamatory cytokines and antitumor immune reactions within the tumor milieu [54]. Also, tumor-evoked Bregs express activated STAT3 and induce TGFβ conversion of Tregs from resting T cells [55] (Fig.3). Therefore, the production
Interaction between tumor cells and tumor microenvironment mediated by cytokines. Tumor cells and different immune cells including TAMs, Treg cells, DC, Th17 cells, and non-tumor (normal epithelial) cells undergo STAT3 activation under the effect of various cytokines, and in turn produce more cytokines forming a feedback loop. STAT3 also regulates cell proliferation, cell cycle progression, apoptosis, angiogenesis together with immune evasion. Inhibition of STAT signaling could eliminate tumor cells while exerting minimal effect on the normal cells. Preclinical models have validated STAT3 as a target for cancer therapy, although only indirect JAK inhibitors have advanced to clinical trials (Cytokines that induce STAT3 activation are written in bold letters).
and release of various survival factors, including IL-6 as a major activator of STAT3, also serve to block apoptosis in cells during the inflammatory process, keeping them alive in very toxic environments. Unfortunately, at the same time these same pathways serve to maintain cells progressing towards neoplastic growth, protecting them from cellular apoptotic deletion and chemotherapeutic drugs.
It is of importance that activation of STAT3 within tumors is heterogeneous and it has been found that pSTAT3 are highest on the leading edge of tumors and that this is associated with stromal, immune, and endothelial cells. This follows from IL-6 from cancer-associated fibroblasts or myeloid cells that in a feedback loop induces autocrine production of IL-6 and pSTAT3 expression in tumor cells, thus also leading to heterogeneous levels of pSTAT3 [56].
Therefore tumor STAT3 activity can mediate tumor immune evasion and induce tolerance rather than immunity by blocking both the production and sensing of inflammatory signals by components of the innate and adaptive immune systems that have been recently defined as “extrinsic tumor suppressors” [57].
Regarding tumor microenvironment, in physiological conditions the activation of STAT3 is of paramount importance during tissue remodeling in the process of „wound healing“ [58]. As tumor growth also includes tissue damage, the dysregulation of STAT3 in the context of tumor microenvironment has a detrimental effect that instead of wound healing leads to further tissue destruction, together with evasion of immune response.
Oncogenes can only transform cells that have been immortalized by carcinogens or other oncogenes exemplifying the paradigm of multistep carcinogenesis. In this sense, mammal cells transformed by oncogenic src show constitutively active STAT3 and negative-dominant forms of STAT3 block the transforming ability of src, demonstrating a close correlation between STAT3 activation and the oncogenic transformation by this oncogene [59].
Moreover, recent studies have shown that constitutive activation of STAT3 in human breast cancer cells correlates with EGFR family kinase signaling and also with aberrant JAK and Src activity [60]. In addition to Src, many other transforming tyrosine kinases, such as Eyk, Ros and Lck, constitutively activate STAT3 in the context of oncogenesis. Another example of tumorigenic stimuli known to activate STAT proteins is Abl that may constitutively activate STAT3 and STAT5, whereas the fusion protein, Bcr-Abl, may activate them in the absence of constitutive JAK activation, showing that the presence of the JAK kinases is not always essential for STAT activation [2] (Table 4).
In addition to its previously characterized nuclear roles, transformation specific function for mitochondrial STAT3 has now been shown. Although previous data implicated a Ras-STAT3 axis in transformation, those cases were in the context of activated tyrosine kinases, such as NPM-ALK [61], RET [62], or autocrine cytokine signaling requiring STAT3 function in the nucleus. However, it has now been shown that for cellular transformation and anchorage-independent growth induced by activated H-, N- or K-Ras, STAT3 phosporylated on Serine727 and expressed exclusively in mitochondria was required. In contrast, recent findings also show that mitochondrially restricted STAT3 did not support src-driven anchorage-independent growth, consistent with former data that src requires nuclear functions of STAT3 [63].
Cell type | Oncogene | Activated STATs |
Fibroblasts | v-Src c-Src v-Sis v-Ras v-Raf IGF-1 receptor | STAT3 STAT3 STAT3 STAT3 |
Myeloid | v-Src | STAT1, STAT3, STAT5 |
T cell | Lck | STAT3, STAT5 |
Mammary/Lung epithelial | v-Src | STAT3 |
Gallbladder adenocarcinoma | v-Src | STAT3 |
Pre-B lymphocytes | v-Abl | STAT1, STAT5 |
Erythroleukemia/blast cells/ basophils/mast cells | Bcr-Abl | STAT1, STAT5 |
Primary bone marrow | Bcr-Abl | STAT5 |
STAT activation by oncogenes
Mitochondrial STAT3 contributes to Ras-dependent cellular transformation by augmenting electron transport chain activity, particularly that of complexes II and V, accompanied by energy production to favor cytoplasmatic glycolysis that represents a hallmark of cancer formulated in the 1950’s by Warburg [64]. Additional analyses are required to understand the connections between glycolysis and oxidative phosphorylation affected by STAT3 in the presence or absence of oncogenic Ras.
STAT3 apparently enters mitochondria associated with GRIM-19 that was identified as a subunit of the mitochondrial complex I and Ser727 appears to be needed for their interaction [65].
Therefore, the “metabolic shift” important for tumor growth mediated by mitochondrial STAT3 may reflect exploitation of a normal function and in this sense mitochondrial STAT3 function could provide a new target for therapeutic approaches to cancer [65].
STAT1 has been considered to be an anti-oncogene, i.e., tumor-suppressor protein that blocks proliferation and induces apoptosis [66]. Moreover, it has been shown that its dysfunction leads to the loss of immune surveillance [67]. Loss of STAT1 supports angiogenesis and metastasis of tumors.
It has been established that STAT1, the first STAT to be discovered, is required for signaling by the IFNs which in addition to their role in innate immunity, serve as potent inhibitors of proliferation and promoters of apoptosis. The involvement of STAT1 in growth arrest and apoptosis in many cell types may be explained by its capacity to induce caspase and p21 expression [68] and reduce c-myc expression. Although, normally, high p21 expression is associated with cell growth arrest, p21 increase has also been observed in some human neoplasias. This contradiction has been explained by Bowman et al. (2000) [2] with the fact that p21 is also responsible for the correct association of the cyclin D1/CDK cyclin complex, and thus its increase may be necessary for cell-cycle progression. Interestingly, in mammary cells p21 upregulation by STAT1 appears to involve BRCA1, which is often lost in familial and other forms of breast cancer. Effective STAT1-BRCA1 binding is mediated by serine phosphorylation of STAT1. More recently besides its role as tumor suppressor, new evidence has shown that STAT1 can be activated in some malignancies such as breast, lung, head and neck cancer and brain tumors [46]. In this sense, STAT1 tyrosine 701 phosphorylation increase was demonstrated in human breast tumor cells with elevated levels of HER-2/Neu as well as in cell lines transfected with HER-2/Neu gene [70]. However, it is of interest that breast cancer patients with higher levels of phosphorylated and DNA-bound STAT1 show better prognosis and live longer.
Besides increased STAT activation, high expression of the unphosphorylated form of STAT1 was also found in cancer cells. Moreover, it has been also shown that recurrent tumors express higher levels of unphosphorylated STAT1 compared to the original tumors [72], as well as cancer cells resistant to ionizing radiation and anticancer agents [73]. Recently, functions of some STAT1-induced genes in cancer cells have been investigated, and some have been shown to have pro-metastatic, pro-proliferative, or antiapoptotic properties [74]. In this sense it has been found in melanoma cells that high levels of STAT1 expression inhibits caspase 3/7 activation in response to doxorubicin which contributes to patients\' resistance to this chemotherapeutic agent [75]. It has also been shown by Khodarev et al. (2007) [76] that ectopically increased expression of STAT1 can induce a radiation-resistant phenotype.
Both type I and type II IFNs increase STAT1 expression in many cell types, including normal fibroblasts and mammary epithelial cells, and the newly synthesized STAT1 protein persists for many days after IFN stimulation in unphosphorylated form [77]. Certain types of human tumors are unresponsive to IFNs due to defects in the STAT1 activation pathway.
Contrary to these findings, recent data states that the expression level of STAT1 does not influence the response to IFN adjuvant therapy in cancer [72] and that the overexpression of STAT1 in recurrent tumors might be caused by IFN treatment. In these tumor cells the found increase in STAT1 level does not result in enhanced anticancer effects of STAT1 as many IFN-induced pro-apoptotic and antiproliferative proteins as APO2L/TRAIL and IRF1 [78] are not upregulated in resistant cells. This strongly indicates that IFN signaling is not responsible for STAT1 upregulation in cancer cells. It has also been found that high level of unphosphorylated STAT1 in tumors protects cancer cells from DNA damage [79].
These observations suggest that increased levels of unphsphorylated STAT1 might participate in oncogenesis as well as resistance to cell death by inducing target genes that increase proliferation, decrease cell death, or increase repair of DNA damage. Increased DNA damage in cancer is due to oncogene-induced damage, chromosome instability, and other causes that are intrinsic to tumorigenesis. Therefore, evolving cancer cells must learn to resist the consequences of DNA damage, avoiding normal cellular responses such as cell cycle arrest or apoptosis, thus relying on support mechanisms that are characteristic for the tumor “stress phenotype”. A working hypothesis that is now being formulated is that the increase in STAT1 expression in cancers is due to processes intrinsic to tumorogenesis [77].
Although STAT3 was originally identified as an acute phase response factor that is activated after stimulation by interleukin-6 (IL-6) [65], the biological functions of STAT3 are diverse, in part stemming from the activation of STAT3 by a wide range of cytokines, growth factors, as well as oncogenes. Among its many effects, it is now known to promote oncogenesis, while a hypermorphic allele of STAT3 can function as an oncogene [10].
It is established that the basic role of STAT3 in tumors is the prevention of apoptosis that is achieved by increased expression of antiapoptotic molecule, Bcl-2, or by affecting cell cycle progression by increased expression of c-myc and cyclin D1 engaged in the transition through G1/S check point. This is a characteristic of tumor cell lines with deleted STAT3 gene (STAT3 -,-) where the lack of STAT3 activity leads to the appearance of apoptosis due to an increase in the level of caspases, and a decrease in the level of Bcl-2, while down-regulated proliferation follows from decreased level of cycline D i c-myc oncogenes.
In contrast to normal cells, in which STAT tyrosine phosphorylation occurs transiently, it has been determined that STATs 1, 3, and 5 are persistently tyrosine phosphorylated in most malignancies (particularly STAT3) [2, 46]. The mechanisms by which STAT3 is persistently or constitutively tyrosine phosphorylated in cancers include increased production of cytokines and cytokine receptors, which is initiated by tumor cells in an autocrine, and by tumor microenvironment in a paracrine manner, by a decrease in the expression of the SOCS proteins through gene promoter methylation, as well as loss of tyrosine phosphatase activity [11].
Most of the described oncogenic functions of STAT3 depend on the phosphorylation status of Tyr705, however, another role of STAT3 is independent of tyrosine phosphorylation, as unphosphorylated STAT3 can also affect gene expression in the nucleus, one mechanism is through binding to NF-κB and mediating its nuclear import [80].
STAT3 has been directly linked to human cancer as it is required for cell transformation by the src oncogene [81], as well as in promoting cellular transformation by the H-ras oncogene. This function, which is dependent on the noncanonical serine phosphorylation of STAT3, takes place in mitochondria.
Unlike another member of STAT family, STAT1, that is imported in the nucleus only in phosphorylated form, STAT3 dynamically shuttles in and out of the nucleus independent of its tyrosine phosphorylation status [82, 83]. Nuclear import requires binding of STAT3 to an importin-α−importin-β dimer. On the other hand, mitochondrial import could be mediated in several ways, including by association with the cytosolic chaperones, heat shock proteins (Hsp70, Hsp90) [84] or associated with GRIM-19, a subunit of mitochondrial complex I of the electron transport chain [85] engaged in cell death processes in mitochondria that when overexpressed inhibits the activity of STAT3 by direct binding [86].
In light of this finding and the fact that STAT3 function has been linked to cancer, Gough et al. (2009) [48] evaluated the contribution of STAT3 to Ras oncogenic transformation. Ras protooncogenes become constitutively active oncogenes with the acquisition of specific point mutations [87], which stabilize Ras binding to guanosine 5´-triphosphate (GTP), thus allowing Ras in its GTP-bound state to stimulate numerous downstream effectors. However, Ras oncogenes can only transform cells that have been immortalized by carcinogens or other oncogenes, in the classical multistep carcinogenesis. Some of the signaling molecules activated in response to Ras can impact the STAT3 transcription factor. For example, mitogen-activated protein kinases (MAPKs) can phosphorylate STAT3 on Ser727 and downstream activation of the NF-κB transcription factor induces autocrine IL-6 production canonical tyrosine phosphorylation of STAT3 [88].
Cancer cells tend to have reduced oxidative phosphorylation in mitochondria, and have increased glycolysis in the cytoplasm leading to lactate production [89]. STAT3, inspite of its role in cellular transformation and cancer, promotes oxidative phosphorylation in mitochondria. New findings show that Ser727 phosphorylation of STAT3 contributed to oxidative phosphorylation in mitohondria. The effect of STAT3 on oxidative phosphorylation in mitochondria was investigated by comparing enzyme activity in STAT3+/+ to STAT3−/− cells [48]. Wegrzyn et al. (2009) [90] showed that STAT3+/+ cells had comparatively greater activity of electron transport complex I and complex II but no difference in the activities of complex III or complex VI. Comparing Ras-transformed STAT3+/+ and STAT3−/− cells revealed that, the presence of STAT3 increased activities of electron transport complex II and V. Analogous to cells that lack oncogenic Ras [90], STAT3 appears to stoke the powerhouse, i.e., mitochondria.
Unexpectedly, STAT3-expressing cells also had decreased mitochondrial membrane potential and increased lactate dehydrogenase production, indicating a shift to cytoplasmic glycolysis. Additional analyses are required to understand the complex connections between glycolysis and oxidative phosphorylation affected by STAT3 in the presence or absence of oncogenic Ras.
Originally, STAT5 was originally identified as a specific transcription factor that mediates the effects of prolactin [91]. STAT5A and STAT5B forms are 96% conserved at the protein level but they differ in their C terminal domain as STAT5A has 20 and STAT5B 8 unique amino acids in the C-terminus [92]. However, STAT5A transmits predominantly the signals initiated by the prolactin receptor, while STAT5B mediates the biological effects of growth hormone.
The most important role of STAT5A and STAT5B is in lymphoid, myeloid and erythroid cell development and function as they are activated by multiple cytokines, including IL-2, IL-3, IL-5, IL-7, IL-9, IL-15, GM-CSF and erythropoietin [93]. STAT5B serine 193 is a novel cytokine induced phospho-regulatory site that is constitutively activated in primary hematopoietic malignancies [94]. Following cytokine stimulation, human STAT5A and STAT5B are phosphorylated by JAK1, JAK2 or Tyk on the conserved tyrosine residues 694 and 699, respectively, which allows for their dissociation from the receptor complex, formation of hetero- or homo-dimers, and nuclear translocation to bind specific elements in the promoter of target genes and activate transcription [95]. While tyrosine phosphorylation is a part of activation signal, the serine 726 on STAT5A and 731 on STAT5B phosphorylation may abrogate the transcriptional activity of STAT5A/B [96].
In addition to the physiological role of STAT5 in hematopoietic cell development, dysregulation of the STAT5 signaling pathway plays a role in oncogenesis and leukemogenesis [97]. Specifically, STAT5 has been shown to be constitutively activated in several forms of lymphoid, myeloid and erythroid leukemia [98-100]. Persistent activation of STAT5 was found to be a result of deregulated cytokine signaling [101] or the presence of oncogenic tyrosine kinases. STAT5 proteins can activate many oncogenic tyrosine kinases, including Bcr-Abl, mutated forms of Flt-3 and Kit, and the JAK2 V617F mutant [102-104]. In acute promyelocytic leukemia (APL) beside the most common PML-RARα chromosomal translocation, RARα gene can be fused with STAT5B forming a fusion protein that blocks myeloid differentiation [105].
The most probable molecular mechanism by which STAT5 promotes tumorogenesis is upregulation of cyclin D and c-myc expression which promotes progression from the G1 to the S-phase of the cell cycle [2]. Aside from stimulating proliferation, STAT5 inhibits apoptosis by inducing the expression of anti-apoptotic Bcl-xl protein and promotes survival of tumor cells [106].
In addition to several types of leukemia and hematopoietic disorders [8], active STAT5A/B is also frequently detected in solid tumors, such as prostate cancer, breast cancer, uterine cancer, squamous cell carcinoma of the head and neck [107].
STAT5A/B controls viability and growth of prostate and breast cancer. The expression of nuclear, active STAT5A/B is often associated with high grade prostate cancer, predicts early disease recurrence and promotes metastatic dissemination. In prostate cancer, active STAT5A/B signaling pathway increases transcriptional activity of androgen receptors. Androgen receptor, in turn, increases transcriptional activity of STAT5A/B. STAT5A/B potentially contributes to castration resistant growth of prostate cancer [108]. The molecular mechanisms underlying constitutive activation of STAT5 in primary and recurrent human prostate cancers are currently unclear, and may involve the autocrine prolactine–JAK2 pathway [109], Src kinases, or Rho GTPases.
In breast cancer, the role of STAT5A/B is more complex. In rodent model systems STAT5A/B may promote malignant transformation and enhance growth of breast tumors [110], while in contrast, STAT5A/B activation in established human breast cancer positively correlates with tumor differentiation [111], prevents metastatic dissemination, and predicts favorable clinical outcome [112] of node-negative breast cancer. In addition, active STAT5A/B, induced by Akt-1, positively correlated with mammary epithelial cell differentiation and possibly a better response to endocrine therapy [113]. Collectively, these studies suggest a dual role for STAT5A/B in the mammary gland as an initiator of tumor formation, as well as a promoter of differentiations of established tumors.
In addition to individual roles of each STAT, they may be coactivated in cancers. In this sense, STATs 1, 3, and 5 are simultaneously tyrosine phosphorylated in a number of human cancers including breast, lung, and head and neck tumors (Table5). The presence of pSTAT5 in addition to pSTAT3 in head and neck tumors can enhance tumor growth and invasion and may contribute to resistance to EGFR inhibitors and chemotherapy [114].
The functional interplay between activated STAT3 and STAT5 has also been described in breast cancers. Considering that STAT3 is included in breast development in association with EGFR, it has been shown on breast cancer cell lines and primary tumors that EGFR mutations, as well as the activity of src proto-oncogene, lead to hyperactivity and STAT3 oncogenic properties [115]. JAK/STAT3 signaling pathway is required for growth of CD44+CD23- breast cancer stem cells in tumors [116]. It has been shown that STAT1 blocking by EGFR in this tumor, unlike inhibition of STAT3, does not show any influence on cell proliferation [117].
Activated STAT3 and IL-6 are preferentially found in triple-negative breast cancers or in high-grade tumors and are associated with poor response to chemotherapy [118]. In human tumors, however, the presence of pSTAT5 is found predominantly in well-differentiated estrogen receptor (ER)–positive tumors and is associated with favorable prognosis. Furthermore, the presence of pSTAT5 is a predictive factor for endocrine therapy response and strong prognostic molecular marker in ER-positive breast cancer. Tumors expressing both activated STAT3 and STAT5 were more likely to be ER positive and human EGFR2 negative and of a lower stage.
Aside from the detected STAT dysregulation in tumors, more recent data report STAT status in peripheral blood lymphocytes (PBL). Results of an investigation of STATs in PBL of patients with breast cancer indicates constitutive, as well as stage-dependent, decrease in STAT1, STAT3, STAT5 expression and impaired induction of these proteins by Th1 cytokines [119]. The commonly found dysfunction of NK cells in breast cancer patients [120-122] is probably the consequence of cytokine dysbalance due to the prevalence of immunosuppressive cytokines such as IL-10 and TGFβ [123], as well as tumor-produced inhibitory factors [124]. This finding is in concordance with the only previous study published for breast cancer patients [125] and also with several other investigations showing STAT dysregulation in PBL of melanoma and renal cell carcinoma patients [126,127]. Moreover, we showed that breast cancer patients’ T and NK cell subsets have lower pSTAT1 level that could be a biomarker of decreased NK cell cytotoxicity and IFNγ production associated with progression of this disease [120, 128,129].
Constitutively active STAT3 present in breast cancer and many human solid tumors, is associated with immunosuppression of the host immune response. STAT3 expression promotes the production of IL-1β, IL-6, IL-10, TGFβ and VEGF by tumor cells [130] leading to STAT3 activation in immune cells and in turn production of more cytokines forming a feedback loop. These cytokines also inhibit dendritic cell maturation, exerting a pro-tumor response. In this sense, evaluation of STATs in PBL is of importance in predicting the possibility of immunomodulatory and antitumor effect of immunotherapy with cytokines in patients with malignancies.
Constitutive activation of STATs has been detected in human head and neck squamous carcinoma cells [131]. In these cells, activation of STATs is dependent on TGFα induced activation of EGFR and studies utilizing antisense oligonucleotides have demonstrated that STAT3 mediates oncogenic growth of these cells. Activation of STATs in non-small cell lung carcinoma (NSCLC) increased production of TGFα by activating EGFR tyrosine kinase [132] induces downstream STAT3 activation and engages it in the pathogenesis of this malignancy. EGFR constitutive activation of STATs has also been detected in prostate, renal cell, lung, ovarian, and pancreatic cancers, as well as melanomas.
In addition, activation of src also occurs with elevated frequency during progression of human breast, ovarian and prostate cancer, and EGFR and Src have been shown to cooperate in human breast cancer [133]. Aside from that, it is of importance that in prostate cancer cell lines the role of BRCA1 gene has been shown in forming of hyperactive STAT3 [134]. When castration resistant disease develops in androgen receptor (AR) positive prostate cancer, these tumors often express higher levels of AR, possibly through activated STAT3, which can transcriptionally regulate AR. Thus, combining antiandrogens with anti- STAT3 drugs should be considered, rather than with chemotherapy in hormone-refractory metastatic prostate cancer [11]. Also, in B16 mouse melanoma cell line hyperactive STAT3 has also been detected [135] (Table 5).
STAT hyperactivity has been demonstrated in lymphomas and leukemias. In acute myeloid leukemia (AML), characterized by the presence of immature myeloid cells in the bone marrow, STAT3 and STAT5 hyperactivity has been found. This may follow from an overproduction of hematopoietic cytokines by tumor cells [136]. An increased level of STAT3β isoform in leuekimic blasts in the bone marrow has been found in patients with this leukemia that have an overall shorter time of survival [137]. It is presumed that STAT5 in AML is activated by mutations in the flt-3 gene. It has also been shown that hyperactive STAT3 induces increased production of VEGF in bone marrow of acute and chronic leukemia. This is in accord with the common finding of increased blood vessel density in bone marrow in these malignancies [138]. Constitutive activation of STATs 1 and 5 has been additionally detected in acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) cells possessing the activated Bcr-Abl tyrosine kinase [139]. Moreover, T cell leukemia that arise in HIV infections, as well as Hodgkin’s disease, express active STAT3.
Tumor type | Activated STAT proteins | |
Solid tumors | ||
Breast cancer | STAT1,STAT3, STAT5 | |
Head and neck cancer | STAT1,STAT3, STAT5 | |
Melanoma | STAT3 | |
Lung cancer | STAT3,STAT5 | |
Ovarian cancer | STAT3 | |
Pancreatic cancer | STAT3 | |
Prostate cancer | STAT3,STAT5 | |
Hematological malignancies | ||
Acute myelogenous leukemia | STAT1,STAT3 | |
HTLV-1 dependent leukemia | STAT3,STAT5 | |
Multiple myeloma | STAT1,STAT3, STAT5 | |
Acute lymphoblastic leukemia | STAT5 | |
LGL leukemia | STAT3 | |
Chronic myelogenous leukemia | STAT5 | |
Lymphomas | ||
Cutaneous T cell lymphoma | STAT3 | |
EBV-related and Burkitt\'s lymphoma | STAT3 | |
B-cell non-Hodgkin\'s lymphoma | STAT3 | |
Anaplastic LGL lymphoma | STAT3 |
Activated STAT proteins found in various solid and hematologic tumors
The constitutive activation of STAT3 is more striking than STAT5 in ALK+ anaplastic large T-cell lymphoma (ALCL). In Sezary Syndrome, a leukaemic form of cutaneous T cell lymphoma (CTCL), the JAK3-STAT3 pathway is constitutively activated, while STAT5 activation is inducible [140]. In APL, aside from characteristic RARα - PML chimeric fusion protein, the novel translocation resulting in STAT5B - RARα is considered to be responsible for the lack of response to ATRA-mediated prodifferentiation therapy [141]. Moreover, inadequate activity of STAT4 leads to T helper 2 (Th2) cytokine (IL-4, IL-5 and IL-10) production and prevents adequate antitumor immune response.
As malignant tumors are now treated, aside from standard chemo and radiation therapy, by novel therapeutic approaches based on tumor molecular profile, therapy of different tumors now includes agents for specific targeted therapy designed to neutralize pathogenic mutations, a goal that is complex and in development. For this reason, novel therapy has extended to transcription factors, such as STATs, and agents have been designed that directly or indirectly block oncogenic STAT3 and STAT5 activity.
Following extensive cell-based screening systems for these agents in different normal, gene modified and malignant cell lines, as well as studies in experimental animals, it has been established that oncogenic STATs may be inhibited in a direct manner. One of the means is by decreasing STAT gene expression by antisense oligonucleotides (DNA and RNA) or by blocking STAT3 and STAT5 activity by small inhibitory molecules and peptide analogues. These STAT inhibitory agents have been most commonly designed to target the domains responsible for STAT dimerization, i.e., the N-terminus domain and the Src homology (SH2) domain, as well as the DNA-binding domain that makes physical contact with the STAT-responsive elements in the promoters of target genes [142] (Figure 4).
Available approaches and strategies to target STAT signaling pathways. These approaches target directly or indirectly STAT signaling in tumors and include interfering with STAT3 and/or STAT5 expression, phosphorylation, degradation, inhibition of receptor and non-receptor tyrosine kinases, direct interaction with STAT proteins intended to disrupt dimerization, and finally approaches to inhibit DNA-binding activity and gene transcription. These strategies should lead to a decrease in STAT signaling activity and even lower their level to normal values.
On the other hand, hyperactive STAT molecules can also be inhibited indirectly by inhibiting up-stream, either receptor or non-receptor tyrosine kinases that drive tyrosine phosphorylation and activate STATs leading to their hyperactive state [143]. In this sense, aside from JAK enzyme inhibitors, in use are also inhibitors of src oncogene and inhibitors of EGFR enzymatic activity, including tyrosine kinase inhibitor gefitinib, and imatinib, an inhibitor of bcr-abl oncogene characteristic for CML, as well as passive immunotherapy with antibody for IL-6 or its receptor [47].
JAK enzyme inhibitors, such as tyrphostine AG490, have been shown in clinical trials to be effective in the therapy of multiple myeloma and other hematological malignancies and solid tumors with aberrant activation of the JAK-STAT signaling pathway [144]. Other agents of this type, including ruxolitinib, by showing promising results in phase III clinical trials for myelofibrosis provide a basis for their study in solid tumors such as prostate cancer. In addition to improved outcome, many JAK inhibitors have been found to be tolerable with no adverse impact on the quality of life of patients possibly due to redundancies in signaling downstream of cytokine receptors, with STATs being only a part of the signaling network.
Considering both the crosstalk between STAT and other signaling pathways and activation of other pathways by STAT inhibiting agents, such as activation of Erk MAPK kinases during pimozide STAT5 inhibitor therapy, therapeutic modalities may include STAT inhibitors in combination with MEK inhibitors, an approach defined as complementary signaling pathway inhibition [145]. Although STAT inhibitors may decrease expression of pro-survival genes, this may not be sufficient to induce apoptosis, but may merely lower the threshold for apoptosis. In this sense, a STAT inhibitor may reduce resistance to cytotoxic agents or ionizing radiation and may best be used in combination with standard therapies.
Other indirect methods for inhibition include modulation of the activity of STAT molecule by using their natural negative regulators. Thus, the activity of these signaling molecules is suppressed by increased protease activity, especially for hyperactive STAT5, induction of nuclear and cytoplasmatic STAT inhibitory proteins, SOCS and PIAS, respectively, or up-regulation of tyrosine-phosphatases that dephosphorylate them [146]. Application of statins, as trichostatin A, leads to inhibition of enzyme histone deacetylase (HDAC) that by decreasing STAT transcriptional activity promotes apoptosis of malignant cells, whereas direct binding of statins to STATs leads to their covalent modification and enhanced degradation [147].
In this sense, different approaches in the context of modern targeted therapy of malignancies by decreasing expression, phosphorylation, dimerization or DNA binding of STATs can decrease the activity of these important signaling molecules or down-regulate them to almost normal level. Considering that inhibition of STAT3 and STAT5 leads to growth arrest and selective apoptosis of tumor cells, sparing benign cells, this approach may be of importance not only in the therapy, but also in chemoprevention of tumors. These aspects of molecular targeted therapy of cancer patients need to be validated in additional, properly designed clinical trials.
As STAT proteins are involved in regulating fundamental biological processes, including apoptosis and cell proliferation that are known to be dysregulated in tumors, it is not surprising to frequently find defects in STAT signaling pathways in malignancies. In the past few years advances have been made in understanding molecular mechanisms that are responsible for STAT protein dysregualtion in different malignant diseases. The critical role of constitutively active STAT3 and STAT5 in tumorogenesis has now been definitely established. Aside from that, STAT1, 3 and 5 can be considered as molecular markers for early detection of certain tumors, as well as prognostic parameters for evaluation of tumor aggressiveness and response to various types of therapies.
Obtained data that associate these molecules with tumor development support the use of STATs as molecular targets in the therapy and chemoprevention of malignancies. Inhibition of oncogenic STATs represents a comprehensive approach in tumor therapy that leads to decreased cell proliferation, survival, angiogenesis and evasion of immune response. Blocking of constitutively active STATs in tumors allows the destruction of tumor cells with minimal effect on normal cells. It is of importance that this type of molecular therapy that inhibits hyperactive STATs can potentiate response to chemo or radiation therapy and may have great potential in the therapy of solid tumors and leukemia. The efficacy of STAT inhibitors in oncological therapy remains still to be evaluated in numerous undergoing and future clinical trials.
This study was supported by the Ministry of Education, Science and Technological development of the Republic of Serbia through grants 41031 and 175056. The authors would like to thank Dr. Milica Apostolović Stojanović for excellent assistance in the preparation of this manuscript.
Most of the developing countries seek to maximise the benefits of foreign direct investments (FDI) to improve economy growth and to encourage foreign investment in both the public and private sectors. As a result, policymakers’ direct resources at incentives aimed at attracting FDI flows because according to [1], FDI quality is also associated with positive and economically significant growth effects. The other perception is that FDI inflows will significantly improve technology and management practices as well as increase capital formation in a host country. As part of its investment drive, the South African government has embarked on a series of activities which include trips to Europe, Asia and across Africa to build an “investment book” to help plug a substantial shortfall of foreign and local direct investment. The purpose was to unlock a $100-billion investment plan to stimulate economic growth which was plummeted as a result of political and policy uncertainty which damaged both the investment and business confidences during the previous regime when the country’s credit rating was slashed to junk by two of the top three agencies and economic growth slowed to a crawl [2, 3].
Such an initiative is anchored on the notion that foreign investment can enable the growth of businesses and creation of job opportunities that would not arise if reliant only on domestic investment. The idea is that the increase in foreign investment can have a spillover effect on the domestic firms, stimulates the economy and positively impacts the economic growth [4]. Therefore, attracting and encouraging FDI and domestic investments remain one of the priority goals of governments in most developing countries including South Africa.
Amongst the characteristics of globalisation is the unrestricted capital flow and access to world market. It has been established that the global FDI stocks have been on the increase (see [5, 6]). Many more African countries are becoming more open to FDI; however, it still remains low [7]. South Africa is amongst the top three countries within the sub-Saharan region which is taken as favourable destinations for FDI. That been the case, the country continues to promote FDI through its various investment promotion strategies. One such initiative is the Promotion and Protection of Investment Bill of 2013, which is the new effort to improve the quality of FDI flowing to South Africa.
The idea of the new administration to scour the globe for $100 billion in investment is that very same goal of attracting and increasing FDI into South Africa which was set in the past seems to be far from being realised because the government may not have done enough to promote it [8]. One of the reasons behind all these is that South Africa remains heavily dependent on foreign investment because of the lower domestic savings between 1994 and the first quarter of 1998 [9]. A total net inflow of capital of R57.4 billion, was realised between 1994 and the first quarter of 1998. However, since then, the long-term capital flows have slowed, and short-term capital has flowed out of the economy, contributing to the depression of the currency (Rand). In 2007, the National Treasury stated that policy reforms would raise investment growth rates, pulling in higher FDI [10].
Despite efforts to attract more FDI into South Africa and other African countries, the [11] global investment trend monitor reports that FDI flow to Africa dropped significantly (31%) in 2015 to an estimated US$38 billion from US$53.9 billion in 2014. This was a result of the largest decline seen by sub-Saharan Africa and Central and Southern Africa. For instance, in 2015, the flow to Mozambique dropped by 21% to US$4.9 billion but notably remains at an estimated US$3.8 billion; Nigeria recorded a reduction by 27% hit by drop in oil price to an estimated US$3.4 billion from US$4.7 billion. South Africa, with its more diversified economy and reputation as an investor-friendly business environment, achieved the highest FDI inflows in Africa during 2014 and 2013, although it should be noted that FDI inflows declined by 33% in 2014 from US$8.3 billion during 2013 to US$5.7 billion during 2014. In addition, South Africa has experienced low projected gross domestic product (GDP) growth rates in the past few years and often faces issues such as prolonged industrial actions, policy uncertainty relating to the mining industry and power shortages which make investors weary of the future of the economy.
The decline and relatively weak performance in FDI attraction happened during the period where the potential attractiveness of South Africa is regarded as high in comparison to other countries in the region and despite progress owing to investment potential in infrastructure [12]. Based on the Global Foreign Direct Investment Country Attractiveness (GFICA) Index, the country is ranked at position 45 out of 109 countries with a 50.5% GFICA index value. This puts it on the second position after Mauritius amongst its peers. The GFICA ranking history shows that it was ranked at number 48 in 2015, number 50 in 2016, number 44 in 2017 and number 45 in 2018 [13].
Furthermore, South Africa has experienced a decelerated growth for a longer time. This is attributed to several factors such as the declining global competitiveness, growing political instability and a weakened rule of law that in 2017 contributed to the country’s investment-grade credit rating to be downgraded to junk status and denting the investor confidence. The government is thus confronted with the challenge of maintaining macroeconomic stability whilst facing a combination of rising public debt, inefficient state-owned enterprises and spending pressures [14]. The other school of thought argues that the weakened growth has been exacerbated by low commodity prices and the allegations of extreme corruption which contributed to political turmoil that helped to plunge the economy into recession in 2017. Furthermore, the situation was worsened by the fact that the economy slipped into a technical recession during the second quarter of 2018 where GDP shrank by 0.7% quarter on quarter (seasonally adjusted and annualised) after a revised 2.6% contraction in the first quarter of 2018 [14].
Just like any other developing country, South Africa is desperately in need of more investments in order to achieve some of its macroeconomic objectives. Even though several such studies such as [15, 16, 17] focused on several determinants of FDI, it appears that very little seems to be known about the drivers of international investment decisions in the South African context. Apart from contributing to policymaking and contribution to the existing body of knowledge, this study might benefit several stakeholders such as academia, government institutions and the policymakers.
As indicated by [18], South Africa, just like the rest of the world, is still in the formative stage of coming to grips with analytical challenges and policy quandaries associated with today’s much more complicated realm of trade and investment. Bailey [19] also made suggestions for future research that stress a call for further contextualisation of the relationship. Moreover, this study is influenced by [20] who pointed out that there has been little investigation of FDI decision processes, most of which focused on strategic decision processes, although some research takes the neoclassical economic approach to microeconomic rational choice and behavioural FDI decision-making. Therefore, the purpose of this study was to investigate drivers of international investment decisions in South Africa. In order to achieve its objectives, several proxies for drivers of international investment decisions were used to determine the impact of investment drivers on FDI.
The chapter is planned as follows: Section 2 presents literature review, whilst research methodology and model are discussed in Section 3; the empirical results and discussions are presented in Section 4 and conclusion of the study summarised in the last section.
The empirical literature produces divided views about the contribution of FDI in the host countries. Those who support the view that it has a positive impact on economic growth consider that there are different ways that produce positive contribution. Ndiaye and Xu [21] contended that FDI comes along with increased competition which will lead to increased productivity, efficiency and investment in human or physical capital. Such a competition can also lead to changes in the industrial structure through more competitive and more export-oriented activities. Another advantage is the benefit the training, which may lead to increased workforce training and managerial skills and thirdly the connection, where foreign investments are often accompanied by technology transfer. Finally, there is a possibility for domestic firms to mimic advanced technologies used by foreign firms.
On the other hand, some scholars have questioned the role of FDI in the host country’s economy. A study by [22] argued that the deterioration of external imbalances is one of the unfavourable effects of FDI inflows in developing countries. Other researchers such as [23, 24] postulated that the damaging and undesirable effects of FDI may be worsened if the technology transferred is inappropriate for developing countries and if FDI crowds out local investors. Others argued that its impact growth can be limited by the local conditions existing in the host developing countries such as the levels of human capital, financial development and institutional quality.
Despite the dichotomy about the contributions of FDI on the economy, its underlying drivers differ according to countries’ locations. However, it is evident that a minimum set of factors must be present in the location for FDI to flow [17]. It could be assumed that investors would select an economy where profitability is expected to be high. However, in an extensive study on the factors influencing FDI, [16] posited that investors not only consider profitability when making investment decisions; other critical factors are taken into consideration such as availability of natural resources, institution environment, country risk, infrastructure availability, costs and the skills of workers. Empirical studies have tested various variables that can potentially attract or repel FDI. Such variables include market-driven variables such as rate of return and labour cost; structural variables, such as infrastructure development and political stability; and macroeconomic policies formulated to achieve economic growth, taxation and price stability.
A study by [25] found that FDI liberalisation is amongst the factors that affect FDI in Africa especially in the long term. Asiedu [26] argued that a good investment framework contributes to higher FDI for African countries. Hooda [15] studied the effects of FDI on the Indian economy between 1991 and 2008 using multiple regression models. The results indicated that the significant factors that determine FDI in developing countries are corporate taxes, labour costs, interest rates, stable political environment, exchange rates, infrastructural facilities and inflation.
As pointed out by [12], South Africa has many attractive assets for investors such as an important demography; a diversified, productive and advanced economy; abundant natural resources; a transparent legal system; and a certain political stability. In addition to the level of attractiveness, it is ranked number 82nd out of 190 economies in [27]’s Ease of Doing Business Score and Ease of Doing Business Ranking. However, as pointed out by [12], the country suffers from a high crime rate, increasing social unrest (strikes and demonstrations), high levels of corruption and structural issues in electricity supply and logistics.
The study employed the bound testing autoregressive distributed lag (ARDL) approach proposed by [28] to investigate drivers of international investment decisions in South Africa.
This study used a quarterly time series data covering the period 2007–2017 obtained from the South African Reserve Bank and Quantec EasyData. FDI which a is net foreign direct investment as a percentage of GDP is a function of income levels (disposable income of households), labour productivity, infrastructure investment (measured by the gross fixed capital formation) interest rates (prime lending rates) and labour unrest.
Labour unrest was used as a dummy variable to capture the effects of labour unrests (strikes) which is a common phenomenon in the South African economy. For the period 2007–2011, the dummy variable will have a value of 0 which signifies the negligible incidents of labour unrest, and a value of 1 is used for the period between 2012 and 2017 due to the rise in the number of industrial actions. This is based on [29]’s report that a total of 99 strike incidents were recorded in 2012 as compared to 67 in 2011, 74 in 2010, 51 in 2009 and 57 in 2008. Working days lost amounted to about R3.3 million in 2012 (involving 241,391 employees) as compared to 2.8 million in 2011 (involving 203,138 employees). In terms of wages lost, R6.6 billion was lost in wages of striking workers during 2012.
The assumption is that foreign investors are sceptical to invest in nations where there is widespread industrial action. Santander Trade Portal [12] also noted that there were more concerns with the increased labour strikes in recent years because it is one of the points which rating agencies have warned could further lower South Africa’s credit rating.
The functional form of the regression model is presented as follows:
where
The decision to use FDI as a proxy for international investment decisions in Eq. (1) was based on [20]’s notion that the FDI decision-making process is influenced by the multinational enterprises’ context in which decision-makers are situated, the type of a decision, and the investment project are situated.
Furthermore, Eq. (1) is expressed in a linear form with some of the variables being expressed as logarithms presented as follows:
where α is a constant,
The estimation technique followed a three-step modelling procedure, namely, testing for order of integration by means of unit root tests, the bounds cointegration test and Granger causality analysis. In addition, the model was taken through a battery of diagnostic and stability tests also known as stability testing to assist in deciding whether or not it has been correctly specified. The modelling procedure is as follows:
The procedure was employed to examine the order of integration of variables which is a crucial step for setting up an econometric model and to do inference. The stationarity or otherwise of a series can strongly influence its behaviour and property. A time series data is stationary if it has a constant mean, constant variance and constant auto-variance for each given lag [30]. The unit root analysis was done by means of a commonly used augmented Dickey-Fuller (ADF) and, in addition, the Dickey-Fuller generalised least squares (DF-GLS) test applied as a confirmatory test. The DG-GLS test formulated by [31] is a modification of the ADF unit root test, and it transforms the time series such that the trend is removed. It involves a two-step process, in which the time series is estimated by generalised least squares in the first step before a normal Dickey-Fuller test is used to test for a unit root in the second step. This process improves the power of a regular ADF test when the autoregressive parameter is near one.
The bound test analyses were done to model the long-run relationship between sets of variables. This procedure was preferred over the [32] cointegration procedure because it can be applied when series have different orders of integration. Following [28] the bound test procedure is applied by modelling the long-run equation as a general vector autoregressive (VAR) model of order p, in
with
where the (k + 1) × (k + 1) are matrices.
contain the long-run multipliers and short-run dynamic coefficients of VECM.
In case we established a long-run relationship amongst the variables, the conditional VECM is specified as follows:
and the conditional VECM of the interest can be specified as:
where
The purpose of this test is to examine the cause and effect relationship between variables. This investigates whether the direction of causality is from economic growth to credit extension, economic growth to household savings or household savings leading to credit extension and vice versa. Granger causality test can be described as the relationship between cause and effect. Basically, the term “causality” suggests a cause and effect relationship between two sets of variables, say, Y and X. Recent advances in graphical models and the logic of causation have given rise to new ways in which scientists analyse cause-effect relationships. Causality is tested amongst the variables that are found to be cointegrated [33]. In econometrics sense, causality is somewhat different to the concept in everyday use; it refers more to the ability of one variable to predict the other. The relationship between variables can be captured by a VAR model. The problem is to find an appropriate procedure that allows us to test and statistically detect the cause and effect relationship amongst the variables. [34] developed a relatively simple test that defined causality as follows: A variable is said to Granger-cause if it can be predicted with greater accuracy by using past values of the variable rather not using such past values, all other terms remaining unchanged.
The purpose of this test was to examine the cause and effect relationship between variables. Based on [33] the hypothesis is that variable
It is assumed that both
Diagnostic testing was used to determine whether any of the assumptions of the classical normal linear regression model are violated, in other words to examine the goodness of fit of the model. The study engaged a battery of residual tests such as normality test, serial correlation, and heteroskedasticity.
As far as stability testing is concerned, the cumulative sum (CUSUM) and cumulative sum of squares (CUSUMSQ) tests for parameter stability were first introduced into the statistics and econometrics literatures by [35]. The test is based on the analysis of the scaled recursive residuals and has the significant advantage over the Chow tests for not requiring prior knowledge of the point at which the hypothesised structural break takes place [36]. In addition, the Ramsey’s “regression specification test” (RESET) tests for misspecification of the functional form. This test helps to investigate the possibility that the dependent variable may be of a non-linear form [37].
This section presents the results of all the empirical tests performed towards the investigation of drivers of international investment decisions in South Africa.
The ADF and DG-GLS unit root tests were carried out at level and at first differences using intercept and intercept and trend. The results are presented in Tables 1 and 2 as follows:
Variables at level | Model level | Lag length | Variables at 1st difference | Lag length | Order of integration | ||
---|---|---|---|---|---|---|---|
LFDI | Intercept | −6.909 (−2.937)** | 0 | ΔInFDI | −7.057 (−2.946)** | 3 | I(0) |
Trend & Intercept | −7.044 (−3.527)** | 0 | −7.002 (−3.540)** | 3 | I(0) | ||
LiL | Intercept | −1.120 (−2.943)** | 3 | ΔInIL | −30.037 (−2.943)** | 2 | I(1) |
Trend & Intercept | −8.035 (−3.527)** | 0 | −10.155 (−3.529 ** | 0 | I(0) | ||
LPL | Intercept | −1.082 (−2.937)** | 0 | ΔInPL | −4.786 (−2.939)** | 0 | I(1) |
Trend & Intercept | −2.231 (−3.527)** | 0 | −4.024 (−3.540)** | 3 | I(1) | ||
LInfInv | Intercept | −1.560 (−2.937)** | 1 | ΔInInfInv | −4.655 (−2.939)** | 1 | I(1) |
Trend & Intercept | −2.9379 (−3.527)** | 1 | −4.680 (−3.530)** | 1 | I(1) | ||
Intr | Intercept | −1.371 (−2.960)** | 9 | ΔIntr | −2.974 (−2.964)** | 9 | I(1) |
Trend & Intercept | −2.731 (−3.563)** | 9 | −5.798 (−3.553)** | 6 | I(1) | ||
LD | Intercept | −1.000 (−2.937)** | 0 | ΔLU | −6.245 (−2.939)** | 0 | I(1) |
Trend & Intercept | −1.973 (−3.527)** | 0 | −6.161 (−3.530)** | 0 | I(1) |
ADF Unit root test results.
0.10 significance level.
0.05 significance level, Indicates critical value at 5% significance level.
0.01 significance level.
Notes: I(1) Indicates unit root at first difference being stationary.
I(0) Indicates unit root in level being stationary.
Variables at level | Model level | Lag length | Variables at 1st difference | Lag length | Order of integration | ||
---|---|---|---|---|---|---|---|
InFDI | Intercept | −6.999 (−1.949) | 0 | ΔInFDI | −10.790 (−1.949) | 0 | I(0) |
Trend & Intercept | −7.175 (−3.190) | 0 | −6.587 (−3.190) | 3 | |||
InIL | Intercept | 2.786 (−1.950) | 3 | ΔInIL | −9.199 (−1.950) | 0 | I(0) |
Trend & Intercept | −7.576 (−3.190) | 0 | −9.287 (−3.190) | 0 | |||
InPL | Intercept | −0.859 (−1.949) | 0 | ΔInPL | −4.704 (−1.950) | 0 | I(1) |
Trend & Intercept | −2.166 (−3.190) | 0 | −4.820 (−3.190) | 0 | |||
InfInv | Intercept | −0.061 (−1.95) | 1 | ΔInInfInv | −3.288 (−1.950) | 0 | I(1) |
Trend & Intercept | −2.597 (−3.190) | 1 | −3.339 (−3.190) | 0 | |||
Intr | Intercept | −1.965 (−1.951) | 5 | ΔIntr | −2.272 (−1.951) | 5 | I(1) |
Trend & Intercept | −2.178 (−3.190) | 5 | −3.319 (−3.190) | 2 | |||
LU | Intercept | −0.661 (−1.949) | 0 | ΔLU | −6.294 (−1.950) | 0 | I(1) |
Trend & Intercept | −1.965 (−3.190) | 0 | −6.321 (−3.190) | 0 |
The unit root results in Tables 1 and 2 indicate a mixture of I(0) and I(1) variables because FDI and income levels were found to be stationary at level, whilst all others became stationary at first difference.
Since the order of integration was found to be mixed and the fact that there was no I [2] variable, the bound test to cointegration was performed, and the results are presented in Table 3. Based on [28] significant levels for lower bound and upper bound are shown as follows:
Test statistic | Value | K |
F-statistic | 9.101 | 5 |
Critical value bounds | ||
Significance (%) | I0 Bound | I1 Bound |
10 | 2.26 | 3.35 |
5 | 2.62 | 3.79 |
2.5 | 2.96 | 4.18 |
1 | 3.41 | 4.68 |
Bound test results.
Our results indicated that the calculated F-statistic of 9.10 is higher than the upper bound critical value 3.38 at the 5% level of significance. Thus, the null hypothesis of no cointegration is rejected, implying the presence of a long-run cointegration relationship amongst the variables. The next step was to examine the expected marginal impacts of the drivers of international investment decisions on international investment decisions in South Africa.
Our empirical evidence in Table 4 reveals that the relationship between all the regressors and FDI is positive but not statistically significant with the exception of the dummy with the p-value of 0.0020 which means it is statistically significant.
Variable | Coefficient | Std. Error | t-Statistic | Prob. |
IL | 0.254 | 7.948 | 0.032 | 0.975 |
PL | 0.086 | 14.345 | 0.006 | 0.995 |
LGFCF | 0.049 | 12.837 | 0.004 | 0.997 |
INTR | 0.026 | 0.376 | 0.069 | 0.945 |
DUMMY | 11.921 | 3.452 | 3.453 | 0.002 |
C | 161.554 | 91.932 | 1.757 | 0.091 |
R-squared | 0.733 | |||
Durbin-Watson stat | 2.192 | |||
F-statistic | 6.237 |
Estimated Long run results.
Additionally, in Table 4 the coefficient of determination (R2) is 0.732920. The implication is that about 73% of variation in international investment decisions in South Africa is caused by variations in the explanatory variables. The Durbin-Watson statistics of 2.19 shows the absence of serial correlation.
The short-run relationship analysis results in Table 5 show that cointegration is strongly confirmed given that the coefficient of the error correction term (−1.351344) has a negative sign. In line with [38], it shows that any deviation from the long-run equilibrium is corrected at the rate 135% for each period to return to the long-run equilibrium after a shock.
Variable | Coefficient | Std. Error | t-Statistic | Prob. |
D(IL) | 0.343 | 10.739 | 0.032 | 0.974 |
D(PL) | 0.121 | 32.574 | 0.004 | 0.997 |
D(LGFCF) | 0.066 | 17.348 | 0.004 | 0.997 |
D(INTR) | 0.035 | 0.509 | 0.069 | 0.945 |
D(DUMMY) | 0.009 | 4.048 | 0.002 | 0.998 |
D(DUMMY(-1)) | −0.313 | 4.864 | −0.064 | 0.949 |
D(DUMMY(-2)) | −0.342 | 4.923 | −0.069 | 0.945 |
D(DUMMY(-3)) | −13.909 | 4.181 | −3.327 | 0.002 |
CointEq(-1) | −1.351 | 0.168 | −8.049 | 0.000 |
Estimated short run analysis results.
Cointeq = FDI−(0.254 × IL + 0.086 × PL + 0.049 × LGFCF + 0.026 × INTR + 11.921 × DUMMY + 161.555).
Since cointegration has been established, the study proceeded with Granger causality test, and the pairwise Granger causality test results are presented at the Appendix section. It was established that there was no causality between income level and FDI and between interest rate and FDI. Similarly, productivity of labour does not Granger-cause FDI; however, the null hypothesis of granger causality could not be rejected between FDI and labour unrests. A bidirectional causality between them was found. Likewise, Granger causality was established between productivity of labour and the labour unrest.
The results of both diagnostic and stability tests based on statistical estimations are presented in Tables 6 and 7 and Figure 1, respectively.
Test | Null hypothesis | Test statistic | P-Value | Conclusion |
Jarque-Bera | Residuals are normally distributed | 98.724 | 0.000 | We do not reject the H0 because the P-value is greater than the LOS at 5%, hence the residuals are normally distributed. |
Breusch Pargan-Godfrey | No serial correlation | 1.522 | 0.467 | We do not reject the reject H0 because the P-value is greater than LOS at 5%, hence there is no serial correlation. |
Arch | No heteroscedasticity | 0.031 | 0.859 | We do not reject H0 as P- value is greater than LOS at 5%, hence there is no heteroscedasticity |
Diagnostic tests results.
Value | DF | Probability | |
t-statistic | 3.994 | 24 | 0.001 |
F-statistic | 15.948 | (1, 24) | 0.001 |
Ramsey RESET test results.
Stability test results.
The residuals are normally distributed, and there is no serial correlation. In the presence of heteroskedasticity, the null hypothesis is rejected (homoscedasticity), and the alternative is accepted.
The results of stability test are presented in Table 7 and Figure 1, respectively.
Based on the summary of results presented in Table 7, the null hypothesis of Ramsey RESET test shows that the model is correctly specified. In tandem with the Ramsey RESET test, the stability test results reveal that after incorporating the CUSUM and CUSUM of squares tests, ARDL model was found to be stable throughout the period of study.
The plot of the cumulative sum of recursive residuals (CUSUM) and cumulative sum of squares recursive residuals (CUSUMQ) of the model presented in Figure 1 indicates stability in the coefficients over the sample period as they fall within the critical bounds indicated by the 5% significance parameters.
The study investigated drivers of international investment decisions in South Africa by means of time series secondary data from the South African Reserve Bank and Quantec EasyData. The bound testing autoregressive distribution lag approach and the Granger causality analysis were employed to achieve the aim of the study.
The long-run analysis revealed that all the regressors have a positive relationship with FDI, but they were not statistically significant with the exception of the dummy with the p-value of 0.0020 which means it is statistically significant. Whilst the outcomes of this study about a positive association between FDI and some of the regressors like labour productivity, interest rates and infrastructural investment seem to be in line with studies such as [39, 40, 41], respectively, the findings of a positive relationship between FDI and labour unrest seem to be in inconsistent with [42] who found that labour unrest has a negative impact on FDI. The presence of cointegration was confirmed by the short-run analysis which also confirmed that any deviation from the long-run equilibrium is corrected to return to the long-run equilibrium after a shock. On the other hand, the pairwise Granger causality test results showed bidirectional causality between FDI and labour unrests.
Empirical findings suggest that government should ensure stable macroeconomic policies. Likewise, policies which promote increase in labour productivity should be encouraged, and labour disputes that result into prolonged strike actions must be minimised; hence consideration of modifying labour laws and regulations is submitted.
Null Hypothesis | Obs | F-Statistic | Prob. |
IL does not Granger Cause FDI | 39 | 1.019 | 0.371 |
FDI does not Granger Cause IL | 0.098 | 0.907 | |
PL does not Granger Cause FDI | 39 | 0.882 | 0.423 |
FDI does not Granger Cause PL | 1.3819 | 0.265 | |
InfInv does not Granger Cause FDI | 39 | 0.461 | 0.635 |
FDI does not Granger Cause InfInv | 0.256 | 0.776 | |
Intr does not Granger Cause FDI | 39 | 1.477 | 0.243 |
FDI does not Granger Cause Intr | 0.446 | 0.644 | |
LU does not Granger Cause FDI | 39 | 0.414 | 0.6645 |
FDI does not Granger Cause LU | 9.883 | 0.0004 | |
PL does not Granger Cause IL | 39 | 1.512 | 0.235 |
IL does not Granger Cause PL | 3.347 | 0.047 | |
InfInv does not Granger Cause IL | 39 | 0.918 | 0.409 |
IL does not Granger Cause InfInv | 0.513 | 0.603 | |
Intr does not Granger Cause IL | 39 | 0.597 | 0.556 |
IL does not Granger Cause Intr | 1.743 | 0.190 | |
LU does not Granger Cause IL | 39 | 1.923 | 0.162 |
IL does not Granger Cause LU | 2.543 | 0.094 | |
InfInv does not Granger Cause PL | 39 | 1.116 | 0.339 |
PL does not Granger Cause InfInv | 9.164 | 0.001 | |
Intr does not Granger Cause PL | 39 | 6.003 | 0.006 |
PL does not Granger Cause Intr | 3.472 | 0.043 | |
LU does not Granger Cause PL | 39 | 1.784 | 0.183 |
PL does not Granger Cause LU | 1.221 | 0.308 | |
Intr does not Granger Cause InfInv | 39 | 5.156 | 0.011 |
InfInv does not Granger Cause Intr | 1.114 | 0.339 | |
LU does not Granger Cause InfInv | 39 | 4.243 | 0.023 |
InfInv does not Granger Cause LU | 1.274 | 0.293 | |
LU does not Granger Cause Intr | 39 | 0.168 | 0.846 |
Intr does not Granger Cause LU | 1.563 | 0.224 |
These Terms and Conditions outline the rules and regulations pertaining to the use of IntechOpen’s website www.intechopen.com and all the subdomains owned by IntechOpen located at 5 Princes Gate Court, London, SW7 2QJ, United Kingdom.
',metaTitle:"Terms and Conditions",metaDescription:"These terms and conditions outline the rules and regulations for the use of IntechOpen Website at https://intechopen.com and all its subdomains owned by Intech Limited located at 7th floor, 10 Lower Thames Street, London, EC3R 6AF, UK.",metaKeywords:null,canonicalURL:"/page/terms-and-conditions",contentRaw:'[{"type":"htmlEditorComponent","content":"By accessing the website at www.intechopen.com you are agreeing to be bound by these Terms of Service, all applicable laws and regulations, and agree that you are responsible for compliance with any applicable local laws. Use and/or access to this site is based on full agreement and compliance of these Terms. All materials contained on this website are protected by applicable copyright and trademark laws.
\\n\\nThe following terminology applies to these Terms and Conditions, Privacy Statement, Disclaimer Notice, and any or all Agreements:
\\n\\n“Client”, “Customer”, “You” and “Your” refers to you, the person accessing this website and accepting the Company’s Terms and Conditions;
\\n\\n“The Company”, “Ourselves”, “We”, “Our” and “Us”, refers to our Company, IntechOpen;
\\n\\n“Party”, “Parties”, or “Us”, refers to both the Client and ourselves, or either the Client or ourselves.
\\n\\nAll Terms refer to the offer, acceptance, and consideration of payment necessary to provide assistance to the Client in the most appropriate manner, whether by formal meetings of a fixed duration, or by any other agreed means, for the express purpose of meeting the Client’s needs in respect of provision of the Company’s stated services/products, and in accordance with, and subject to, the prevailing laws of the United Kingdom.
\\n\\nAny use of the above terminology, or other words in the singular, plural, capitalization and/or he/she or they, are taken as interchangeable.
\\n\\nUnless otherwise stated, IntechOpen and/or its licensors own the intellectual property rights for all materials on www.intechopen.com. All intellectual property rights are reserved. You may view, download, share, link and print pages from www.intechopen.com for your own personal use, subject to the restrictions set out in these Terms and Conditions.
\\n\\nWe employ the use of cookies. By using the IntechOpen website you consent to the use of cookies in accordance with IntechOpen’s Privacy Policy. Most modern day interactive websites use cookies to enable the retrieval of user details for each visit. On our site, cookies are predominantly used to enable functionality and ease of use for those visiting the site.
\\n\\nIn no circumstances shall IntechOpen or its suppliers be liable for any damages (including, without limitation, damages for loss of data or profit, or due to business interruption) arising out of the use, or inability to use, the materials on IntechOpen's websites, even if IntechOpen or an IntechOpen authorized representative has been notified orally or in writing of the possibility of such damage. Some jurisdictions do not allow limitations on implied warranties, or limitations of liability for consequential or incidental damages; consequently, these limitations may not apply to you.
\\n\\nIntechopen.com website content and services are provided on an "AS IS" and an "AS AVAILABLE" basis. Material appearing on www.intechopen.com could include minor technical, typographical, or photographic errors. IntechOpen may make changes to any material contained on its website at any time without notice.
\\n\\nIntechOpen has no formal affiliation to any external sites that link to www.intechopen.com, unless otherwise specifically stated. As such, it is not responsible for content that appears on any such sites. The inclusion of any link to IntechOpen does not imply endorsement by IntechOpen. Use of any such linked website is done solely at the user's own discretion.
\\n\\nWe reserve the right of ownership over our entire website www.intechopen.com, and all contents. By using our services, you agree to remove all links to our website immediately upon request. We also reserve the right to amend these Terms and Conditions and our linking policy at any time. By continuing to link to our website, you agree to be bound to, and abide by, these linking Terms and Conditions.
\\n\\nIf you find any link on our website, or any linked website, objectionable for any reason, please Contact Us. We will consider all requests to remove links but will have no obligation to do so.
\\n\\nWithout prior approval and express written permission, you may not create frames around our web pages or use other techniques that alter in any way the visual presentation or appearance of our website.
\\n\\nIntechOpen may revise its Terms of Service for its website at any time without notice. By using this website, you are agreeing to be bound by the current version of all Terms at the time of use.
\\n\\nThese Terms and Conditions are governed by and construed in accordance with the laws of the United Kingdom and you irrevocably submit to the exclusive jurisdiction of the courts in London, United Kingdom.
\\n\\nCroatian version of Terms and Conditions available here
\\n"}]'},components:[{type:"htmlEditorComponent",content:'By accessing the website at www.intechopen.com you are agreeing to be bound by these Terms of Service, all applicable laws and regulations, and agree that you are responsible for compliance with any applicable local laws. Use and/or access to this site is based on full agreement and compliance of these Terms. All materials contained on this website are protected by applicable copyright and trademark laws.
\n\nThe following terminology applies to these Terms and Conditions, Privacy Statement, Disclaimer Notice, and any or all Agreements:
\n\n“Client”, “Customer”, “You” and “Your” refers to you, the person accessing this website and accepting the Company’s Terms and Conditions;
\n\n“The Company”, “Ourselves”, “We”, “Our” and “Us”, refers to our Company, IntechOpen;
\n\n“Party”, “Parties”, or “Us”, refers to both the Client and ourselves, or either the Client or ourselves.
\n\nAll Terms refer to the offer, acceptance, and consideration of payment necessary to provide assistance to the Client in the most appropriate manner, whether by formal meetings of a fixed duration, or by any other agreed means, for the express purpose of meeting the Client’s needs in respect of provision of the Company’s stated services/products, and in accordance with, and subject to, the prevailing laws of the United Kingdom.
\n\nAny use of the above terminology, or other words in the singular, plural, capitalization and/or he/she or they, are taken as interchangeable.
\n\nUnless otherwise stated, IntechOpen and/or its licensors own the intellectual property rights for all materials on www.intechopen.com. All intellectual property rights are reserved. You may view, download, share, link and print pages from www.intechopen.com for your own personal use, subject to the restrictions set out in these Terms and Conditions.
\n\nWe employ the use of cookies. By using the IntechOpen website you consent to the use of cookies in accordance with IntechOpen’s Privacy Policy. Most modern day interactive websites use cookies to enable the retrieval of user details for each visit. On our site, cookies are predominantly used to enable functionality and ease of use for those visiting the site.
\n\nIn no circumstances shall IntechOpen or its suppliers be liable for any damages (including, without limitation, damages for loss of data or profit, or due to business interruption) arising out of the use, or inability to use, the materials on IntechOpen's websites, even if IntechOpen or an IntechOpen authorized representative has been notified orally or in writing of the possibility of such damage. Some jurisdictions do not allow limitations on implied warranties, or limitations of liability for consequential or incidental damages; consequently, these limitations may not apply to you.
\n\nIntechopen.com website content and services are provided on an "AS IS" and an "AS AVAILABLE" basis. Material appearing on www.intechopen.com could include minor technical, typographical, or photographic errors. IntechOpen may make changes to any material contained on its website at any time without notice.
\n\nIntechOpen has no formal affiliation to any external sites that link to www.intechopen.com, unless otherwise specifically stated. As such, it is not responsible for content that appears on any such sites. The inclusion of any link to IntechOpen does not imply endorsement by IntechOpen. Use of any such linked website is done solely at the user's own discretion.
\n\nWe reserve the right of ownership over our entire website www.intechopen.com, and all contents. By using our services, you agree to remove all links to our website immediately upon request. We also reserve the right to amend these Terms and Conditions and our linking policy at any time. By continuing to link to our website, you agree to be bound to, and abide by, these linking Terms and Conditions.
\n\nIf you find any link on our website, or any linked website, objectionable for any reason, please Contact Us. We will consider all requests to remove links but will have no obligation to do so.
\n\nWithout prior approval and express written permission, you may not create frames around our web pages or use other techniques that alter in any way the visual presentation or appearance of our website.
\n\nIntechOpen may revise its Terms of Service for its website at any time without notice. By using this website, you are agreeing to be bound by the current version of all Terms at the time of use.
\n\nThese Terms and Conditions are governed by and construed in accordance with the laws of the United Kingdom and you irrevocably submit to the exclusive jurisdiction of the courts in London, United Kingdom.
\n\nCroatian version of Terms and Conditions available here
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From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. 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