Reversible phosphorylation of proteins, executed by kinases and phosphatases, is the major posttranslational protein modification in eukaryotic cells, causing them to become activated or deactivated. This intracellular event represents a critical regulatory mechanism of several signaling pathways and can be related to a broad number of diseases, including cancer. Few decades ago, protein tyrosine phosphatases (PTPs) were considered as tumor suppressors. However, nowadays, accumulating evidence demonstrates that a misregulation of PTP activities plays a crucial and decisive role in cancer progression and metastasis. In this chapter, we will focus on the molecular aspects that support the crucial role of PTPs in cancer and in turn make them promising for prediction, monitoring, and rational appropriate therapy selection of individual patients.
- protein tyrosine phosphatases
- cancer hallmarks
- tumor suppressor
- epithelial-mesenchymal transition
Protein tyrosine phosphorylation plays a key role in cellular biology, once it can create a new recognition site for protein-protein interactions, control protein stability, and specify the protein location, and, more importantly, regulates enzymatic activity. Therefore, this intracellular event represents a critical regulatory mechanism of several signaling pathways and, once it is dysregulated, can be related to a broad number of diseases, including tumor development. Reversible phosphorylation of proteins is controlled reciprocally by both protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). These phosphatases are hydrolases that preferentially act on phosphotyrosine residue of a wide range of proteins, having as products dephosphorylated protein at tyrosine residue and inorganic phosphate. PTPs consist of a large protein superfamily with 107 members that can be divided into four families (class I, II, III, and IV) according to differences in the amino acid sequence at their catalytic domains and the amino acid used in the catalytic reaction, cysteine-based PTPs (class 1, 2, and 3) and aspartate-based PTPs (class 4) [1, 2]. So far, most of PTPs have been reported to act as tumor suppressors; however, some PTPs can also act as oncogenes depending on the tumor stages or the expression of their interacting partners.
Along human tumor development, cells acquired biological plasticities that were firstly defined by Hanahan and Weinberg, as hallmarks of cancer. These authors proposed some capabilities of cancer cells that contribute for the disease complexity, aggressiveness, and invasiveness: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, deregulating cellular energetics, avoiding immune destruction, and activating invasion and metastasis . Surprisingly, in the last decade, some reports have shown the relevance of PTPs for tumor cell plasticities. In this chapter we aim to draw an organized picture of the molecular mechanisms by which PTPs take part on tumor biological plasticity acquisition (Figure 1).
2. PTPs modulate energetic metabolism in tumors
Under normal conditions, cell metabolism depends on a tightly coordinated regulation of key regulatory enzymes and, consequently, metabolic pathways responsible for converting nutrients into building blocks for synthetic macromolecules, energy production, and biomass. However, cancer cells display efficiency capacity in reprogramming their metabolism through genetic or epigenetic changes in order to get survival, proliferation, migration, invasiveness, and resistance to death stimuli . In recent years, it has been demonstrated that PTPs display a key role in favoring cancer cell metabolic plasticity.
2.1 PTPs and Warburg effect
Otto Warburg showed that tumor cells substantially metabolize glucose to lactate, even with the availability of oxygen. Under normal conditions, glucose is metabolized to pyruvate by a series of enzymatic steps in the glycolytic pathway, which is subsequently oxidized by the TCA and respiratory chain, generating CO2, H2O, and 32 or 34 molecules of ATP per glucose molecule, while in glycolysis, 2 ATPs/glucose are produced. This alteration in glucose metabolism depends on increased transcription of GLUTs, glycolytic enzymes, and oncogenes and increased demand of mitochondrial metabolism for biosynthetic processes [4, 5, 6].
Until a few years ago, the importance of protein kinases for the Warburg effect had been focused on several studies. However, recently, in the discovery that PTPs also have relevance in tumor onset and progression, attention has been given to the role of these phosphatases in tumor metabolism, as it is the case of Cdc25A, LMWPTP, PRL-3, and PTEN.
2.2 PTPs and glutamine/lipid metabolism
Some tumor cells become “addicted” to glutamine, once this amino acid can provide energy and substrates necessary for cell division. As a consequence, the tumor increases the mass of tumor cells and controls the potential redox through the synthesis of NADPH . PTEN knockdown, in prostate cancer, reduces the protein level of GLS, enzyme involved in the glutaminolysis pathway, and increases the FASN expression . Tumor cells also exhibit substantial alterations in lipid metabolism. During fast growth and aggressive progression, tumor cells required many metabolic intermediates and coordinate the activation of lipid synthesis leading to membrane formation, energy storage, and second messenger production [17, 18].
3. PTPs favor tumor growth through survival positive regulation, and cell death resistance
While normal cells tightly control the synthesis, secretion of growth factors, and proliferative signaling pathways, in order to ensure cellular homeostasis, cancer cells carry one or more defects along the signaling pathways from extracellular compartment, for example, growth ligands and their receptors, to intracellular mediators, such as PI3K, MAPK, and Akt, which give them survival advantages [19, 20]. In this context, PTPs’ overexpression through gene amplification, loss, or inhibition contributes for aberrant signaling and, in turn, promoting tumor cell survival as exemplified below:
During cell transformation to malignancy, tumor cells became expert in overcoming a broad diversity of stresses, such as uncontrolled signaling regulation, starvation, DNA damage, hypoxia, and also anticancer therapy. In this aspect, different researchers have shown that PTPs are involved in tumor cells resistant to chemotherapeutic agents.
4. PTPs contribute for metastasis through extracellular matrix remodeling and epithelial-mesenchymal transition
In this chapter subtitle, we will focus on strategies for migration and invasion as part of the metastasis process.
PTPs activate the extracellular matrix remodeling and epithelial-mesenchymal transition. ECM is a three-dimensional noncellular scaffold crucial for life in multicellular organisms which is dynamically and continuously remodeled. ECM is mainly composed of water and almost 300 proteins, for example, collagens (fibrillar forms such as I–III, V, XI and non-fibrillar forms), proteoglycan (aggrecan and glycosaminoglycan such as heparin sulfate and hyaluronic acid), and glycoproteins (especially elastin, laminins, and fibronectin) [50, 51]. This essential component is considered an extremely organized meshwork in a strict contact with cells providing both biochemical and biomechanical support. It is well known that despite the physical support to cells, ECM also modulates cell differentiation, migration, and proliferation [50, 52]. Therefore, abnormal ECM remodeling (exacerbate deposition or degradation) can be observed during pathological conditions such as fibrosis and cancer [50, 52]. In tumor microenvironment, much of the ECM proteins are produced not only by stroma cells, e.g., cancer-associated fibroblasts , but also tumor cells can produce ECM proteins . Malignant transformation is characterized by changes in the organization of cytoskeleton resulting in abnormal cell signaling related to cell-cell and to cell-ECM adhesion, a phenomenon termed epithelial-mesenchymal transition (EMT). EMT consists of the loss of epithelial cell characteristics to possess properties of mesenchymal cells. Several studies have shown that the EMT contributes to tumor progression, invasion, metastasis, and acquisition of therapeutic resistance. During the EMT process, the cancer cells acquire a fibroblastic morphology with a positive regulation of mesenchymal markers (N-cadherin, vimentin, and α-actin) and a negative regulation of epithelial cell markers (E-cadherin, ZO-1, claudins, occludins, and cytokeratin) as well as a regulation of transcription factors that are associated with increased migratory capacity (Slug, ZEB1/ZEB2, Twist1/Twist2). These factors bind to the E-cadherin gene promoter and repress it [54, 55, 56]. EMT requires a rupture of basement membrane permitting invasion and migration of cancer cells through the ECM, then causing remodeling, and creating a tumor-permissive environment .
Characteristic loss of E-cadherin-mediated cell-cell adhesion is commonly found during malignant transformation  in which process kinases and phosphatases have key roles [59, 60]. Several PTKs, including SRC and EGFR, phosphorylate the cadherin-catenin complex on different residues, resulting in a loss of cell adhesion . For instance, PTP1B regulates cadherin-based adhesion by dephosphorylating β-catenin at Tyr654 . In addition to β-catenin, p120-catenin phosphorylation increases binding and affinity to E-cadherin, and PTPμ appears to be a regulator of p120-catenin phosphorylation status, also acts as a scaffold, and recruits similar and regulatory molecules to sites of cell adhesion [61, 62]. SHP2 is also able to bind to cadherin-catenin complex and integrin molecules .
Cell migration through ECM requires integrin-mediated adhesion as well as turnover of focal adhesions . A decrease in tyrosine phosphorylation by PTPs is involved in the formation and disassembly of focal adhesions. For instance, PTPα is required for the activation of Src kinase following integrin interaction , and the dephosphorylation of p130 CRK-associated substrate, by PTP-PEST, is necessary for disassembly of focal adhesions, enabling cell migration . The relation between PTPs and upstream regulators of cell matrix adhesion and Rho family of small GTPases has also been shown . Most Rho proteins have intrinsic GTPase activity which is stimulated by GTPase-activating proteins (GAPs), and these GAPs are modulated by phosphorylation at tyrosine sites. Consequently, PTPs can influence Rho protein activation through regulating the phosphorylation state of GAPs. Sastry and colleagues showed that PTP-PEST overexpression reduces Rac1 (a kind of G protein) activity resulting in protrusion and retraction during cell migration . On the other hand, SHP2 seems to have some contradictory action, while some literatures reported a RhoA activity inhibition by SHP2  and others suggested a stimulation . In addition, p190RhoGAP, a GAP for RhoA, is a target for SHP-2 and LMWPTP and, in turn, regulating cytoskeletal rearrangement .
Metalloproteinases (MMPs) are one of the most important ECM-remodeling enzymes produced by tumoral cells, which are linked to tumorigenesis and metastasis . More recently, it was reported that MMPs promote cell survival, angiogenesis , and induction of EMT . Hwang and coworkers  observed that the treatment of MCF-7 breast cancer cells with BVT948 (a PTP inhibitor) decreases invasion through suppression of NF-κB-mediated MMP-9 expression. On the converse side, PTPμ knockdowns resulted in elevated adhesion, invasion, and proliferation of breast cancer cells due to activation of ERK and JNK signaling pathway and consequent elevated MMP-9 activity . It was demonstrated that the overexpression of PRL-3 increased the migration and invasion capacity of DLD-1 colorectal cancer cells, which was dependent on the expression of MMP-7 . Maacha and coworkers demonstrated that the contribution of the PTP4A3 for malignancy of uveal melanoma is related to MMP-14 . Yuan and colleagues found that overexpression of PTPN9 reduces invasion and decreases MMP-2 gene expression in MDA-MB-231 cells through inhibition of STAT3 downregulation . Interestingly, still in the context of breast cancer, William Du and his team  analyzed the levels of microRNA-24 in patients with breast carcinoma and found higher content of this microRNA in breast carcinoma samples than in benign breast tissue. They also generated constructs expressing miRNA-24 and studied their functions in vivo and in vitro. In vivo experiments in mice indicated that the expression of miRNA-24 enhanced tumor growth, invasion, and metastasis to the lung and decreased survival. Molecularly, in vitro and in vivo experiments showed high EGFR phosphorylation but repressed expression of PTPN9 and PTPRF due to direct target of these phosphatases by miRNA-24. Consistently, they found in patients with metastatic breast carcinoma a higher phosphorylation of EGFR but lower levels of PTPN9 and PTPRF. Another confirmation was the upregulation of MMP-2 and MMP-11 but downregulation of MMP inhibitor (TIMP-2) which supports the roles of miRNA-24 in tumor invasion and metastasis in breast cancer suggesting miRNA-24 as a potential target for cancer intervention. In another study, Liu and collaborators  observed that PTP1B promotes the aggressiveness of brain cancer through decreasing PTEN levels and, consequently, promoting AKT activation and increasing of MMP-2 and MMP-7. Previously, it was reported that PTP1B promotes gastric cancer cell invasiveness through modulating the expression of MMP-2, MMP-9, and MMP-14 . Another interesting study shows the relationship of PTP1B and interruption of cell adhesion and induction of the
Besides being involved in ECM remodeling by modulating MMP activities, PTPs (PTEN, SHP2, PTP1B, PRL3, PTP1B, PTRB, and PTPN9) have a key role in signaling cascades that promote expression of EMT markers.
5. PTPs that act as tumor suppressors
Tumor suppressors operate in different ways and compartments to limit cell growth and proliferation. Besides the important contribution of PTPs in cancer progression, some PTPs that act as tumor suppressors are described below:
Over the past two decades of research on PTPs, the field has achieved a great progress in understanding the immense role of these phosphatases in cancer progression. Here, we presented an organized picture that clearly shows the participation/contribution of PTPs as key mediators of cancer plasticity, due to their loss of function or overexpression. In summary the above compendium highlights the importance of PTPs not only in cancer progression but also as potential targets for therapeutic interventions. Indeed, during the transition from good to poor outcome of different cancer subtypes, PTPs are extremely plastic, with the capacity to readjust themselves across a wide spectrum of stimuli. This plasticity of PTPs together with the loss of function of PTP suppressors provides tumor cells with all conditions for growth, proliferation, and survival. Illustrative examples are PTEN (loss), LMWPTP, PRL-3, and PTP1B serving as “signaling hubs” that connect different hallmarks (such as sustaining proliferative signaling, evading growth suppressors, resisting cell death, deregulating cellular energetics, and activating invasion and metastasis). This connection might explain, at least in part, the great capacity of tumor cells’ plasticity.
Our research on this field has been supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (grant 2015/20412-7) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (grant 303900/2017-2).
Conflict of interest
The authors declare no conflict of interest.
Appendices and nomenclature
p130 Crk-associated substrate (member of an adapter protein family that binds to several tyrosine-phosphorylated proteins)
also known as
epidermal growth factor receptor
estrogen receptor beta
extracellular signal-regulated kinase
focal adhesion kinase
forkhead box protein O1
glyceraldehyde 3-phosphate dehydrogenase
GTPase-activating proteins or GTPase-accelerating proteins
glucose transporter 1
glycogen synthase kinase 3 beta
H2A histone family member X
Janus kinase 2
lactate dehydrogenase A
low-molecular-weight protein tyrosine phosphatase, also known as ACP1
mitogen-activated protein kinase
mouse embryonic fibroblast
mammalian target of rapamycin
nuclear factor kappa-light-chain-enhancer of activated B cells
pyruvate kinase isozymes M2
phosphatase of regenerating the liver-3, also recognized as PTP4A3
phosphatase and tensin homologue
protein tyrosine kinases
protein tyrosine phosphatase sigma
protein tyrosine phosphatase
PTP-PEST (PTP—proline, glutamic acid, serine, and threonine rich)
tyrosine-protein phosphatase non-receptor type 1
protein tyrosine phosphatase non-receptor type 3
protein tyrosine phosphatase non-receptor type 11
PTP also referred to as FAP1
tyrosine-protein phosphatase non-receptor type 9
protein tyrosine phosphatase receptor delta
protein tyrosine phosphatase receptor type F
receptor-type protein tyrosine phosphatase H, also referred to as stomach cancer-associated protein tyrosine phosphatase-1 (SAP-1)
protein tyrosine phosphatase receptor type O
protein tyrosine phosphatase receptor T
protein tyrosine phosphatases
class of protein called small GTPase
Ras homologue of small
Ras homologue of small
Src homology 2 (SH2) domain-containing inositol polyphosphate 5-phosphatase 1
Src homology 2 (SH2) domain-containing inositol polyphosphate 5-phosphatase 2
Src homology 2 (SH2) domain-containing phosphotyrosine phosphatase, also known as PTPN6
Src homology 2 (SH2) domain-containing phosphotyrosine phosphatase 2, also known as PTPN11
signal transducer and activator of transcription type 3
tricarboxylic acid cycle
transforming growth factor beta
WD-repeat-containing protein 1
zinc finger E-box-binding homeobox ½