Abstract
Epithelial cells develop tight junctions (TJs) and cell polarity. Both properties are sensitive to environmental signals such as the epidermal growth factor (EGF) and the cardiotonic steroid ouabain. EGF is regarded as the main protector against injuries in epithelia, and ouabain is a hormone that regulates blood pressure, natriuresis, cell survival, and cell adhesion. After treatment with epidermal growth factor or ouabain, epithelial dog kidney MDCK cells undergo a drastic remodeling that includes changes in the transcription, translation, localization, and degradation of cell junction proteins. Degradation of these proteins involves selective and nonselective autophagy as well as endocytic lysosomal and proteasomal routes. The remodeling mechanism of tight junction’s proteins includes the activation of Src and ERK1/ERK2 kinases, the phosphorylation and translocation into the nucleus of the transcription factor STAT3, the activation of PKC to induce the endocytosis of claudin-2, and the delivery of this protein to the lysosomes. Whole communicating junctions and desmosomes are internalized by one cell and sent to degradation by nonselective autophagy. Nonselective and selective autophagies in epithelial cells are very context dependent; nevertheless, it is clear that, together with endocytic lysosomal and proteasomal degradation, they play a key role in the remodeling and functioning of cell junctions.
Keywords
- claudin-2
- ouabain
- EGF
- MDCK
- tight junctions
1. Introduction
When multicellular organisms left the sea of constant chemical composition to conquer the land, it became necessary to develop mechanisms to maintain a constant internal milieu similar to the sea that was left behind.
The complex organization and regulation of cell junctions and cell polarity in epithelial cells are adaptations to perform vectorial transport. A given substance crosses epithelial layers either through the
Recent research demonstrated that
Cellular junctions and plasma membrane polarity are highly regulated. For example, a progressive conversion of renal intercalated cells of the collecting tubules from α to β type comprises the inversion of the apical H+-ATPase and a basolateral Cl−/HCO3+ exchanger polarity, in response to the increase in the expression of hensin, a protein of the extracellular matrix [31, 32], and cysts embedded in collagen displace their TJs from the vicinity of the lumen toward the proximity of the external surface [33, 34].
Cell junctions and plasma membrane polarity are crucial for the normal physiology of the organism, and its failure in several pathologies has disastrous consequences. To start with, it is common that the genetic elimination of crucial proteins, such as E-cadherin from the AJs or ZO-2, is lethal at embryonic stages [35, 36], but whenever an epithelial adhesion protein is not expressed, epithelia compartmentalization and vectorial transport are lost. For example, in hereditary familial hypomagnesemia with hypercalciuria and nephrocalcinosis, the lack of CLDN-16 and CLDN-19 impairs Ca2+ and Mg2+ reabsorption in the kidney [17, 37]; in cholestatic children’s liver disease, the absence of ZO-2 and TJs provokes the invasion of bile salts into the blood [38]; in pemphigus vulgaris, the depletion of Des by autoantibodies against the desmosomal cadherin desmoglein-3 results in the formation of skin blisters [39], which can also appear if HDes are disassembled by mutations in the integrin β4, an adhesion molecule of this cell junction [40]; loss of adhesion and augmented proliferation in colon cancer are elicited by mutations that increases the cytosolic and nuclear pools of β-catenin [27]; infection and inflammation boost
2. Cell junctions have a general common layout
All junctions have a similar structural layout: they have transmembrane proteins that are the receptors for adhesion, and a series of membrane-associated proteins that bind the cytoplasmic aspect of transmembrane receptors to the actin, tubulin, or cytokeratin cytoskeleton to provide mechanical strength. Besides cell adhesion, cell junctions are sensors that inform, in and out, the state of extracellular environment to modulate cell’s proliferation, differentiation, and fate. Given that lysosomes are of paramount importance for cell junctions and plasma membrane polarity, it is necessary to briefly review the degradation routes where this organelle intervenes.
3. Lysosome degradation pathways
Lysosomes are major degradative organelles of eukaryotic cells. They were first identified as cell compartments enriched in hydrolases [43], but now they are also recognized as providers of building blocks during starvation and powerful stations to sense nutrients and regulate transcription and cellular homeostasis [44]. Lysosomes have a highly acid lumen (pH 4.5–5.0) produced by a vacuolar H+-ATPase. The acidic pH is necessary for the hydrolysis of waste materials and drives the transport of sugars, amino acids, nucleotides, and lipids, through the single membrane of the organelle for recycling [45]. The lysosomal membrane owes its resistance against the activity of the hydrolases that it contains, to the expression of a prominent glycocalyx in its inner surface, formed by glycosylated transmembrane proteins such as the human LIMP-2 and its homologues in
Many intracellular proteins are ubiquitiated and degraded in the proteasome (Figure 2, 1). There are also several routes to deliver cellular material into the lysosomes: an
A central regulator of lysosomal activity, particularly autophagy, is the target of rapamycin (mTOR), a multi-protein complex that includes the kinase mTOR itself, inhibited by rapamycin, the raptor adaptor, two intrinsic inhibitors of mTOR activity, DEPTOR and PRAS40, and a G-protein. The mTOR complex senses energy and nutrient availability, growth factors, and stress conditions to modify cell growth and proliferation. In normal conditions, mTOR localizes in the cytosol and triggers anabolic programs, like mRNA translation. Under starvation, mTOR is translocated to the cytosolic side of the lysosome membrane, where it initiates catabolic processes like autophagy [44].
A growing body of evidence suggests that lysosomes can function as Ca2+ stores and contact intimately to the endoplasmic reticulum, the peroxisome, and the mitochondria to deliver necessary lipids [61, 62] and that lysosomes can fuse to the plasma membrane to pour hydrolytic enzymes in the extracellular media that modify the extracellular matrix and induce differentiation [59]. Lysosomes induce cell death when its membrane is permeabilized and hydrolases such as cathepsin B, a Ca2+-sensitive protease, are released in the cytoplasm. Cell death induced by lysosomal damage is observed in tissue remodeling, elimination of excessive intracellular waste or metals, and the immune response to intracellular pathogens and neurodegenerative diseases [63, 64].
To maintain compartmentalization and vectorial transport in epithelial cells, the synthesis and degradation of adhesion proteins must be closely coordinated. Nevertheless, epithelial cells must have certain degree of plasticity to modify cell junctions in response to the variable environment. Lysosomal activity is crucial in both situations.
4. Role of lysosomes in the degradation of tight junction proteins
4.1. Biology of tight junctions
TJs, also known as
Epithelia adjust the permeability of their paracellular route in response to physiological requirements, pathological conditions, and pharmacological challenges. One simple way to gaze epithelial permeability is to measure the transepithelial electrical resistance (TER) [92]: the higher the value of TER, the lower the paracellular permeability. On this regard, the renal system is very illustrative. Human kidneys filtrate 170 l of plasma but secrete only 1.7 l of urine. Water, proteins, sugars, and ions from the glomerular filtrate are reabsorbed, and the filtrate is steadily concentrated along the nephron. The epithelia that line this tubular surface in vertebrate species gradually increase their TER from approximately 10 Ω cm2 at the proximal convoluted tubule [93, 94] to several thousands of Ω cm2 at the collecting duct [95, 96] and up to hundreds of thousands of Ω cm2 at the bladder [97, 98]. A number of epithelial cell adaptations account for by this TER gradient: increments in cell size, reduction of the junctional membrane tortuosity, a progressive increase in the structural complexity of TJ strands, and the expression of a specific set of CLDNs in each nephron segment [15, 65]. CLDN-2 induces a low TER phenotype in renal MDCK cells [99], from cation and water-selective channels [83, 100, 101], and it is expressed in proximal tubules [102–104], where it is necessary for the uptake of Na+, water and, likely, Ca2+ [105]. CLDN-4 induces a high-resistance phenotype upon the epithelial cells that express it [106–108], including those at the distal nephron segment epithelium [102–104].
4.2. Autophagy of CLDN-2 participates in the differentiation of epithelia induced by the epidermal growth factor and exerts a protective effect
The fluids that bathe apical membranes, such as urine, semen, and milk, are radically different from each other, but the interstitial milieu that contacts the basolateral membranes has a constant composition maintained by homeostatic mechanisms. This difference suggests that substances in the apical media might regulate specific epithelial properties. Several substances in the extracellular milieu induce TER changes in canine MDCK cells [109]. One of them is EGF [110], a substance previously known to increase the TER of epithelial kidney pig LL-CPK1 cells [111]. Urinary EGF reduces the cellular CLDN-1 and CLDN-2 protein level and increases CLDN-4 one [110]. EGF decreases the cellular level of CLDN-2 [112] through the simultaneous activation of Src kinase, extracellular regulated kinases 1/2 (ERK1/2) [113, 114], and the transcription factor STAT3 [114] that, in turn, may accelerate clathrin-mediated endocytosis and lysosomal degradation of CLDN-2 [113], block CLDN-2 [115], and trigger CLDN-4 [116] transcription in MDCK cells. In lung cancer cells though, EGF increases CLDN-2 through the activation of the EGF/EGFR/MEK and cFos pathway [117]. It would be interesting to find out the molecular mechanisms that fail in cancer and provoke the opposite response.
The response elicited by EGF is transient, reaches a maximal value of TER at 15 h, and slowly decreases to control values at 24 h. This downregulation is provoked by the induction of the synthesis of prostaglandin E2 by the EGF itself that increases AmpC production, which in turn blocks the activation of ERK1/2 [118].
It is not clear which vesicular compartment participates in the CLDN-2 degradation induced by EGF. The observation that the knockdown of Rab14 induces the lysosomal degradation of CLDN-2 in MDCK cells [119] opens the possibility that EGF somehow be able to inactivate this Rab protein.
The induction of CLDN-2 downregulation by EGF is blocked by bafilomycin A1 and chloroquine, indicating that it may be performed by autophagy (Figure 3). A schematic representation of the mechanisms of EGF effect on CLDNs is shown in Figure 4. The induction of selective autophagy by EGF can be seen as a differentiation or protective effect. In this respect, autophagy has been observed in Caco-2 cancer colon cells deprived of nutrients, where selective autophagy of CLDN-2 is activated, resulting in an increase in TER [120]. Moreover, in porcine gut IPEC-1 epithelial cells, the deprivation of nonessential amino acids induces an apoptotic process that degrades CLDN-1 and ZO-1, but if autophagy is inhibited with 3MA, degradation of adhesion proteins and apoptosis is potentiated, indicating that autophagy has a protective role in these cells [121]. Finally, the injured spinal cord in rats induces the degradation of p120 and β-catenins, as well as CLDN-5 and occludin, in blood vessels of endothelia. This degradation is performed through selective autophagy, considering that these proteins associate to LC3II and p62. The administration of retinoic acid potencies autophagy and improves movement of the injured rats [122].
4.3. Ouabain induces degradation of CLDN-2
In the eighteenth century, William Withering used extracts of the herb foxglove (
The activation of the Src-EGFR-ERK1/2 cascade by OUA regulates cell adhesion in a concentration-dependent manner: 10 nM OUA, a concentration near the hormonal level, increases the degree of sealing of the TJs, inducing the transcription, translation, and expression at the TJs of CLDNs [139], and 300 nM or higher concentrations of OUA promote cell detachment resulting from TJ, AJ, De, GAPJ, and FA disassembly, endocytosis, and posterior degradation of their cell adhesion molecules [140]. Occludin, CLDN-2, and CLDN-4 endocytoses are clathrin-dependent [141]. 300 nM but not 10 nM OUA increases p62 signal and its colocalization with CLDN-2 in MDCK cells; degradation of CLDNs at 300 nM OUA is inhibited with NH4Cl and bafilomycin A1 [141], suggesting that ouabain activates CLDN-2 degradation through autophagy (Figure 5). OUA increments the size of intracellular structures that bind an antibody against Rab11, a recycling endosome marker, indicating that OUA is not inducing recycling of CLDN-2 (Figure 6). The mechanism of OUA action is shown in Figure 7.
The final outcome of the treatment with high concentrations of OUA is the detachment and death of OUA-sensitive cells [132, 137, 140, 142]. Ionic imbalance that results from the inhibition of the enzyme has been considered the prime cause of cell death given the fame of the Na+,K+-ATPase as an ion transporter. However, cells do not detach when they are cultured in low K+ medium [137], which mimics the diminished [K+]i content induced by OUA. The cytotoxic action of OUA in humans and rodent cells depends on the features of the type α subunit expressed, rather than by any downstream components of the cell death machinery [142]. In this respect, epithelial cells expressing a OUA-resistant isoform of Na+,K+-ATPase do not detach when they are incubated in low K+- or K+-free medium [137, 143]. Therefore, ionic imbalance by itself is not sufficient to detach cells; OUA and the activation of kinases (p38 tyrosine kinases, Src, and ERK1/2) are necessary (Figure 7), a finding that agrees with the triple role of the Na+,K+-ATPase: transporter, signaling receptor, and cell-cell adhesion molecule [144].
4.4. Autophagy plays a role in claudin-16 degradation in lysosomes
Renal hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive disease characterized by abundant renal Mg2+ and Ca2+ wasting that causes renal parenchymal calcification and renal failure. It can only be cured through renal transplantation. The illness results of the lack of stable expression of CLDN-16 and/or CLDN-19 caused by mutations in
5. Role of lysosomes in the degradation of adherens junctions
5.1. Biology of adherens junctions
In chordates, AJs are Ca2+-dependent cell-cell adhesions between neighboring epithelial cells at the lateral domain, immediately below the TJs (Figure 1, red). In prechordates, AJs present an inverted localization with respect to the TJs: AJs are the most apical junction of the lateral membrane, placed over the septated junctions. AJs consist of the nectin-afadine and the cadherin-catenin complexes. The nectin’s complex forms a scaffold necessary for the assembly of the AJs [156–159], whereas the cadherins serve as homotypic adhesion receptors [160, 161]. The associated plaque proteins catenins and afadins, in turn, bind the receptors to the cytoskeleton of actin [162, 163]. The homotypic adhesion of cadherin plays an important morphogenetic role because it underlays the selection and association of cells of the same type to form specific tissues, a process denominated “cell sorting” [164]. Based on the fact that there are numerous cadherins in the unicellular choanoflagellate
5.2. Endocytic route and selective autophagy degrade key proteins of adherens junctions
In a normal epithelium, β-catenin is mostly associated to E-cadherin at the plasma membrane, and the cytosolic pool of β-catenin is kept low by degradation in the proteasome. However, a proliferation signal, triggered by a Wnt ligand, impedes the β-catenin degradation and induces its accumulation in the nucleus to activate proliferation (Figure 8B) [27]. E-cadherin is degraded by lysosomes through an endocytic route [166]. The cytoplasmic domain of E-cadherin has an endocytosis signal that is normally masked by
6. The peculiar nonselective autophagy mechanisms of degradation of large portions of communicating junctions and desmosomes
6.1. Biology of communicating junctions and desmosomes
GAPJs are molecular ducts that communicate the cytoplasm of contiguous cells and allow the epithelium to respond coordinately to various stimuli or extracellular signals (Figure 1, yellow). These junctions are made up of tetraspan proteins: connexins in chordates and innexins in prechordates [172]. Six connexins polymerize to form a hemichannel or connexon in a cell, which attaches to a connexon in the neighboring cell, forming in this manner an intercellular channel that can be opened by diverse stimuli. The dense clustering of tens to thousands of intercellular channels originates a GAPJ [173–175]. Connexins are associated with a scaffold of ZO-1 or ZO-3, vinculin, Src, and tubulin [176]. This association is important for the localization of connexons, the formation of the multimolecular clusters of intercellular channels in the plasma membrane, and the regulation of intercellular communication [177].
Des are cell-to-cell adhesion structures that confer mechanical strength to epithelia and cardiomyocytes. These junctions are composed of five main proteins: the desmosomal cadherins, desmogleins, and desmocollins are the receptors for adhesion. Their cytoplasmic tails bind to plaque proteins of the armadillo family, plakoglobin and plakophilin (Figure 1) [178]. The armadillo proteins attach to another plaque protein, desmoplakin, which, in turn, links the protein cluster to the cytoskeleton made of intermediary filaments of cytokeratin [179]. Observations in tissues and cultured cells have shown that Des can adopt a Ca2+-dependent adhesion state that progresses to a Ca2+-independent hyper-adhesion state, a process that requires PKC activation [22, 180–182].
6.2. Macromolecular assemblies of communicating junctions and desmosomes are degraded by autophagy
GAPJs are extremely stable junctional structures: as soon as they are formed, they become indestructible [183, 184]. Nevertheless, they are very dynamic due to the fact that connexins have a very short half-life of only 1–5 h [185]. Consequently, there is a permanent turnover that involves the closure of the intercellular conduction by several stimuli, for example, the binding of EGF to its receptor. The central portion of the GAPJ is then internalized, including the bound hemichannels and membrane of the neighboring cell, forming a peculiar structure named annular GAPJ (Figure 9) [186]. In some conditions, annular GAPJ may be recycled back to the plasma membrane [187] although, usually, they are degraded through autophagy; yet, the precise mechanism, the kind of autophagy involved, and the fate of the cells depend on the trigger and/or the cellular context [185, 187–189]. A mechanism that stops autophagy implicates the hijacking of components of the initiation of autophagy, for example, Atg16, by the connexins themselves. On nutrient starvation, connexins release Atg16, the blockade is lost and autophagy proceeds [190].
On liver cells of BRL 3A expressing connexin-43, cadmium inhibits GAPJ intercellular communications and induces the degradation by autophagy of connexin-43 as well as apoptosis. Inhibition of autophagy exacerbates Cd2+-induced inhibition of the intercellular communication and apoptotic cell death [188] revealing the protective role that autophagy plays on cell fate.
Des are also very stable structures which can reach a hyper-adhesion state insensitive to Ca2+ depletion [191]. It has been shown that a half of Des is internalized after extracellular Ca2+ depletion in a PKC- and actin-dependent process [182, 192]. Internalized half desmosome is then transported by kinesins and microtubules toward the centrosome and remains there without recycle to the plasma membrane. Degradation proceeds in lysosomes and proteasomes [193]. In mouse epidermis, the complete Des are engulfed and internalized [192]. Nevertheless, the degradation mechanism is different when disassembly is triggered with autoantibodies from pemphigus vulgaris patients; in this case, Des disassemble in smaller complexes made of the autoantibody, desmoglein-3, and plakoglobin that are endocyted and delivered to the lysosomes through the endocytic route [194].
7. Continuous recycling in focal adhesion requires autophagy
7.1. Biology of focal adhesion and hemidesmosomes
FAs, also known as focal contacts, and HDes are the cellular junctions that attach cells to the extracellular matrix. HDes are common in stratified epithelia and bind epithelial cells to the underlying extracellular matrix (Figure 1, blue) [6] . The adhesion receptors of both, FAs and HDes, are transmembrane proteins of the family of integrins, which exist as heterodimers of α and β subunits form. There are 19 α-integrins and 8 β-integrins that combine to form 25 existing heterodimers in mammals [195, 196]. HDes provide stable adhesion and mechanical resistance to epithelial tissues by anchoring the extracellular matrix to the cytokeratin cytoskeleton, through a protein complex that includes the adhesion receptors α6β4 integrin, BP180, and the tetraspanin CD151, and the intracellular adapter proteins plectin and BP230 [6]. The expression of several HDes proteins depends on the transcription factor SOXF [197]. While the extracellular region of integrins of FAs binds the extracellular matrix, the cytosolic portion contacts specific plaque proteins such as focal adhesion kinase (FAK) and paxillin, which are important signaling proteins. Other protein components of the FA plaque, such as talin, vinculin, and α-actinin, bind the adhesion receptors to the actin microfilaments [5, 198, 199].
7.2. Role of lysosomes in the regulation of focal adhesions
FAs are essential in cell migration and, therefore, for embryogenesis, wound healing, immune cell function, cancer progression, and promoting metastasis [200]. Cell migration requires endocytosis and recycling of integrins given by endocytic signals in its cytoplasmic tail. These signals bind either clathrin or caveolin-1 to induce integrin endocytosis. Once inside the cell, integrins anchored to protein complexes are sent to the early endosomes, where they can be sorted either to late endosomes and lysosomes for degradation (Figure 10, 1) or to recycling endosomes and plasmatic membrane for the assembly of new FAs. A short loop for recycling requires Rab4 proteins and is generally activated in response to growth factors (Figure 10, 2); the long loop is Rab11 and Arf6 dependent and delivers integrins to the perinuclear recycling compartments (PNRCs) and, from there, to the cell membrane (Figure 10, 3) [190]. The actin cytoskeleton is essential to the recycling pathway; in fact, depletion of the actin-related protein (Arp) 2/3 or the nucleating-promoting factors such as the members of the Wiskott-Aldrich syndrome protein (WASP) blocks recycling and induces delivery to the lysosomes [5, 198].
FA disassembly is linked to autophagy in two ways: a nonselective autophagy triggered by extreme stress condition, such as starvation or hypoxia (Figure 10, 4), and a selective autophagy for housekeeping and quality control that includes ubiquitin-tagged substrate association of them with an autophagic cargo receptor (ACR) attached to LC3II. This autophagy provokes the disassemby of FA Under starvation, β1 integrin is degraded in autophagosomes in cervix adenocarcinoma epithelial HeLa cells. This autophagy is inhibited by high mTOR activity at the leading edge during migration, which promotes increased motility [201], whereas the activation of selective autophagy promotes FA disassembly in metastatic mammary epithelial cells (4T1) [202]. Thus, the inhibition of autophagosome reduces cancer cell’s malignancy, indicating that selective authophagy is also a cell migration regulator (Figure 10).
Besides migration, autophagy is linked to anoikis, a type of cell death due to detachment from the substrate. Loss of integrin-mediated adhesion initiates autophagy, which delays anoikis and downregulates apoptotic signals. This process affords cells time to reattach; however, in cancer cells, high autophagic activity after detachment provides resistance and promotes malignancy, allowing the cell to support stress condition, increase motility, and resist anoikis [203, 204].
Although there are several illnesses produced by the lack of HDes protein expression, little is known about HDes degradation.
8. Concluding remarks
Lysosomal degradation mechanisms are crucial for the formation, differentiation, and degradation of epithelial cell junctions. Epithelial cells use selective autophagy to degrade claudin-2, in response to the stimulation with the epidermal growth factor. Ouabain, at a concentration close to the hormonal, does not induce autophagy of tight junction proteins and, at high concentrations though, induces lysosomal degradation that can involve autophagy. The precise sequence of events and outcome of each lysosomal degradation mechanism is context dependent; nevertheless, it is clear that the degradation through macroautophagy of large plaque of complete communicating junctions and desmosomes, as well as of desmosomal halves, takes place either in natural tissues or in cultured cells. It is also clear that the desmosomal transition from weak to strong adhesion stages requires lysosomal activity, that β-catenin undergoes selective autophagy in some conditions and that E-cadherin degradation is performed in lysosomes through an endocytic route.
References
- 1.
Cereijido M, Contreras RG, Shoshani L. Cell adhesion, polarity, and epithelia in the dawn of metazoans. Physiological Reviews. 2004;84:1229-1262. DOI: 10.1152/physrev.00001.2004 - 2.
Cereijido M, Contreras RG, Shoshani L, García-Villegas MR. Membrane targeting. Progress in Biophysics & Molecular Biology. 2003;81:81-115 - 3.
Cereijido M, Gonzalez-Mariscal L, Contreras RG. Epithelial tight junctions. American Review of Respiratory Disease. 1988;138:S17-S21. DOI: 10.1164/ajrccm/138.6_Pt_2.S17 - 4.
Farquhar MG, Palade GE. Junctional complexes in various epithelia. Journal of Cell Biology. 1963;17:375-412 - 5.
Burridge K, Chrzanowska-Wodnicka M. Focal adhesions, contractility, and signaling. Annual Review of Cell and Developmental Biology. 1996;12:463-518. DOI: 10.1146/annurev.cellbio.12.1.463 - 6.
de Pereda JM, Ortega E, Alonso-García N, Gómez-Hernández M, Sonnenberg A. Advances and perspectives of the architecture of hemidesmosomes: Lessons from structural biology. Cell Adhesion & Migration. 2009;3:361-364 - 7.
Cereijido M, Valdés J, Shoshani L, Contreras RG. Role of tight junctions in establishing and maintaining cell polarity. Annual Review of Physiology. 1998;60:161-177. DOI: 10.1146/annurev.physiol.60.1.161 - 8.
Cereijido M, Contreras RG, González-Mariscal L. Development and alteration of polarity. Annual Review of Physiology. 1989;51:785-795. DOI: 10.1146/annurev.ph.51.030189.004033 - 9.
Shoshani L, Contreras RG. Biogenesis of epithelial polarity and the tight junctions. In: Anderson JM, Cereijido M, editors. Tight Junctions. Boston, MA: Springer Science & Business Media. 2007. pp. 165-198 - 10.
Yeaman C, Grindstaff KK, Nelson WJ. New perspectives on mechanisms involved in generating epithelial cell polarity. Physiological Reviews. 1999;79:73-98 - 11.
Gumbiner B, Simons K. A functional assay for proteins involved in establishing an epithelial occluding barrier: Identification of a uvomorulin-like polypeptide. Journal of Cell Biology. 1986;102:457-468 - 12.
Gumbiner B, Simons K. The role of uvomorulin in the formation of epithelial occluding junctions. Ciba Foundation Symposium. 1987;125:168-186 - 13.
Poulsen SB, Fenton RA, Rieg T. Sodium-glucose cotransport. Current Opinion in Nephrology and Hypertension. 2015;24:463-469. DOI: 10.1097/MNH.0000000000000152 - 14.
Chen L, Tuo B, Dong H. Regulation of intestinal glucose absorption by ion channels and transporters. Nutrients. 2016;8:43. DOI: 10.3390/nu8010043 - 15.
Cereijido M, Ruiz O, Gonzalez-Mariscal L, Contreras RG, Balda MS, Garcia-Villegas R. The paracellular pathway: A small version of the kidney nephron. In: Audus KL, Raub TJ, editors. Biological Barriers to Protein Delivery. Boston, MA: Springer Science & Business Media. 1994. pp. 107-125. DOI: 10.1007/978-1-4615-2898-2 - 16.
Price ER, Rott KH, Caviedes-Vidal E, Karasov WH. Claudin gene expression patterns do not associate with interspecific differences in paracellular nutrient absorption. Comparative Biochemistry and Physiology—Part B: Biochemistry & Molecular Biology. 2015;191:36-45. DOI: 10.1016/j.cbpb.2015.09.003 - 17.
Simon DB, Lu Y, Choate KA, Velazquez H, Al-Sabban E, Praga M, et al. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science. 1999;285:103-106 - 18.
Koefoed-Johsen V, Ussing HH. The nature of the frog skin potential. Acta Physiologica Scandinavica. 1958;42:298-308. DOI: 10.1111/j.1748-1716.1958.tb01563.x. - 19.
Cheng CY, Mruk DD. Cell junction dynamics in the testis: Sertoli-germ cell interactions and male contraceptive development. Physiological Reviews. 2002;82:825-874. DOI: 10.1152/physrev.00009.2002 - 20.
Brazil JC, Parkos CA. Pathobiology of neutrophil-epithelial interactions. Immunology Reviews. 2016;273(1):94-111. DOI: 10.1111/imr.12446 - 21.
Thuenauer R, Müller SK, Römer W. Pathways of protein and lipid receptor-mediated transcytosis in drug delivery. Expert Opinion on Drug Delivery. 2016;14(3):1-11. DOI: 10.1080/17425247.2016.1220364 - 22.
Broussard JA, Getsios S, Green KJ. Desmosome regulation and signaling in disease. Cell and Tissue Research. 2015;360:1-12. DOI: 10.1007/s00441-015-2136-5 - 23.
Matter K, Balda MS. Signalling to and from tight junctions. Nature Reviews Molecular Cell Biology. 2003;4:225-237. DOI: 10.1038/nrm1055 - 24.
Kim NG, Gumbiner BM. Adhesion to fibronectin regulates Hippo signaling via the FAK-Src-PI3K pathway. Journal of Cell Biology. 2015;210:503-515. DOI: 10.1083/jcb.201501025 - 25.
Scarpa E, Mayor R. Collective cell migration in development. Journal of Cell Biology. 2016;212:143-155. DOI: 10.1083/jcb.201508047 - 26.
El-Okdi N, Smaili S, Raju V, Shidyak A, Gupta S, Fedorova L, et al. Effects of cardiotonic steroids on dermal collagen synthesis and wound healing. Journal of Applied Physiology. 2008;105:30-36. DOI: 10.1152/japplphysiol.00119.2008 - 27.
Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127:469-480. DOI: 10.1016/j.cell.2006.10.018 - 28.
Huerta M, Muñoz R, Tapia R, Soto-Reyes E, Ramírez L, Recillas-Targa F, et al. Cyclin D1 is transcriptionally down-regulated by ZO-2 via an E box and the transcription factor c-Myc. Molecular Biology of the Cell. 2007;18:4826-4836. DOI: 10.1091/mbc.E07-02-0109 - 29.
Betanzos A, Huerta M, Lopez-Bayghen E, Azuara E, Amerena J, Gonzalez-Mariscal L. The tight junction protein ZO-2 associates with Jun, Fos and C/EBP transcription factors in epithelial cells. Experimental Cell Research. 2004;292:51-66 - 30.
Balda MS, Garrett MD, Matter K. The ZO-1-associated Y-box factor ZONAB regulates epithelial cell proliferation and cell density. Journal of Cell Biology. 2003;160:423-432. DOI: 10.1083/jcb.200210020 - 31.
Takito J, Hikita C, Al-Awqati Q. Hensin, a new collecting duct protein involved in the in vitro plasticity of intercalated cell polarity. Journal of Clinical Investigation. 1996;98:2324-2331. DOI: 10.1172/JCI119044 - 32.
Al-Awqati Q, Vijayakumar S, Takito J. Terminal differentiation of epithelia. Biological Chemistry. 2003;384:1255-1258. DOI: 10.1515/BC.2003.138 - 33.
Barriere H, Chambard M, Mauchamp J, Gabrion J. Polarity reversal of inside-out thyroid follicles cultured within collagen gel: An ultrastructural study. Biology of the Cell. 1986;57:39-51 - 34.
Barriere H, Chambard M, Selzner JP, Mauchamp J, Gabrion J. Polarity reversal of inside-out thyroid follicles cultured within collagen gel: Structure of the junctions assessed by freeze-fracture and lanthanum permeability. Biology of the Cell. 1988;62:133-144 - 35.
Larue L, Ohsugi M, Hirchenhain J, Kemler R. E-cadherin null mutant embryos fail to form a trophectoderm epithelium. Proceedings of the National Academy of Sciences. 1994;91:8263-8267 - 36.
Xu J, Kausalya PJ, Phua DCY, Ali SM, Hossain Z, Hunziker W. Early embryonic lethality of mice lacking ZO-2, but Not ZO-3, reveals critical and nonredundant roles for individual zonula occludens proteins in mammalian development. Molecular and Cellular Biology. 2008;28:1669-1678. DOI: 10.1128/MCB.00891-07 - 37.
Konrad M, Schaller A, Seelow D, Pandey AV, Waldegger S, Lesslauer A, et al. Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement. The American Journal of Human Genetics. 2006;79:949-957. DOI: 10.1086/508617 - 38.
Sambrotta M, Strautnieks S, Papouli E, Rushton P, Clark BE, Parry DA, et al. Mutations in TJP2 cause progressive cholestatic liver disease. Nature Genetics. 2014;46:326-328. DOI: 10.1038/ng.2918 - 39.
Samuelov L, Sprecher E. Inherited desmosomal disorders. Cell and Tissue Research. 2014;360(3):1-19. DOI: 10.1007/s00441-014-2062-y - 40.
Koster J, Kuikman I, Kreft M, Sonnenberg A. Two different mutations in the cytoplasmic domain of the integrin beta 4 subunit in nonlethal forms of epidermolysis bullosa prevent interaction of beta 4 with plectin. Journal of Investigative Dermatology. 2001;117:1405-1411. DOI: 10.1046/j.0022-202x.2001.01567.x - 41.
Nava P, López S, Arias CF, Islas S, Gonzalez-Mariscal L. The rotavirus surface protein VP8 modulates the gate and fence function of tight junctions in epithelial cells. Journal of Cell Science. 2004;117:5509-5519. DOI: 10.1242/jcs.01425 - 42.
Bonilla-Delgado J, Bulut G, Liu X, Cortés-Malagón EM, Schlegel R, Flores-Maldonado C, et al. The E6 oncoprotein from HPV16 enhances the canonical Wnt/β-catenin pathway in skin epidermis in vivo. Molecular Cancer Research. 2012;10:250-258. DOI: 10.1158/1541-7786.MCR-11-0287 - 43.
de Duve C. Lysosomes. Bulletin De l'Academie Royale De Medecine De Belgique. 1958;23:608-618 - 44.
Lim CY, Zoncu R. The lysosome as a command-and-control center for cellular metabolism. Journal of Cell Biology. 2016;214:653-664. DOI: 10.1083/jcb.201607005 - 45.
Forgac M. Vacuolar ATPases: Rotary proton pumps in physiology and pathophysiology. Nature Reviews Molecular Cell Biology. 2007;8:917-929. DOI: 10.1038/nrm2272 - 46.
Li Y, Chen B, Zou W, Wang X, Wu Y, Zhao D, et al. The lysosomal membrane protein SCAV-3 maintains lysosome integrity and adult longevity. Journal of Cell Biology. 2016;215:167-185. DOI: 10.1083/jcb.201602090 - 47.
Schreij AMA, Fon EA, McPherson PS. Endocytic membrane trafficking and neurodegenerative disease. Cellular and Molecular Life Sciences. 2016;73:1529-1545. DOI: 10.1007/s00018-015-2105-x - 48.
Scharaw S, Iskar M, Ori A, Boncompain G, Laketa V, Poser I, et al. The endosomal transcriptional regulator RNF11 integrates degradation and transport of EGFR. Journal of Cell Biology. 2016;261:543-558. DOI: 10.1083/jcb.201601090 - 49.
Marzella L, Ahlberg J, Glaumann H. Autophagy, heterophagy, microautophagy and crinophagy as the means for intracellular degradation. Virchows Arch B Cell Pathol Incl Mol Pathol. 1981;36(2-3):219-34 - 50.
Orenstein SJ, Cuervo AM. Chaperone-mediated autophagy: Molecular mechanisms and physiological relevance. Seminars in Cell and Developmental Biology. 2010;21:719-726. DOI: 10.1016/j.semcdb.2010.02.005 - 51.
Mizushima N, Komatsu M. Autophagy: Renovation of cells and tissues. Cell. 2011;147:728-741. DOI: 10.1016/j.cell.2011.10.026 - 52.
Rabinowitz JD, White E. Autophagy and metabolism. Science. 2010;330:1344-1348. DOI: 10.1126/science.1193497 - 53.
Singh R, Cuervo AM. Autophagy in the cellular energetic balance. Cell Metabolism. 2011;13:495-504. DOI: 10.1016/j.cmet.2011.04.004 - 54.
Schmidt MR, Haucke V. Recycling endosomes in neuronal membrane traffic. Biology of the Cell. 2007;99:333-342. DOI: 10.1042/BC20070007 - 55.
Bucci C, Parton RG, Mather IH, Stunnenberg H, Simons K, Hoflack B, et al. The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway. Cell. 1992;70:715-728 - 56.
Morrison HA, Dionne H, Rusten TE, Brech A, Fisher WW, Pfeiffer BD, et al. Regulation of early endosomal entry by the Drosophila tumor suppressors Rabenosyn and Vps45. Molecular Biology of the Cell. 2008;19:4167-4176. DOI: 10.1091/mbc.E08-07-0716 - 57.
Sönnichsen B, De Renzis S, Nielsen E, Rietdorf J, Zerial M. Distinct membrane domains on endosomes in the recycling pathway visualized by multicolor imaging of Rab4. Rab5, and Rab11. Journal of Cell Biology. 2000;149:901-914 - 58.
Bucci C, Thomsen P, Nicoziani P, McCarthy J, van Deurs B. Rab7: A key to lysosome biogenesis. Molecular Biology of the Cell. 2000;11:467-480 - 59.
Yoshimori T, Yamamoto A, Moriyama Y, Futai M, Tashiro Y. Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells. Journal of Biological Chemistry. 1991;266:17707-17712 - 60.
Sahu R, Kaushik S, Clement CC, Cannizzo ES, Scharf B, Follenzi A, et al. Microautophagy of cytosolic proteins by late endosomes. Developmental Cell. 2011;20:131-139. DOI: 10.1016/j.devcel.2010.12.003 - 61.
Hua R, Cheng D, Coyaud É, Freeman S, Di Pietro E, Wang Y, et al. VAPs and ACBD5 tether peroxisomes to the ER for peroxisome maintenance and lipid homeostasis. Journal of Cell Biology. 2017;16(2):367-377. DOI: 10.1083/jcb.201608128 - 62.
Costello JL, Castro IG, Hacker C, Schrader TA, Metz J, Zeuschner D, et al. ACBD5 and VAPB mediate membrane associations between peroxisomes and the ER. Journal of Cell Biology. 2017;931:331-342. DOI: 10.1083/jcb.201607055 - 63.
Gómez-Sintes R, Ledesma MD, Boya P. Lysosomal cell death mechanisms in aging. Ageing Research Reviews. 2016;32:150-168. DOI: 10.1016/j.arr.2016.02.009 - 64.
Toops KA, Lakkaraju A. Let's play a game of chutes and ladders: Lysosome fusion with the epithelial plasma membrane. Communicative & Integrative Biology. 2013;6:e24474. DOI: 10.4161/cib.24474 - 65.
Claude P, Goodenough DA. Goodenough. Fracture faces of zonulae occludentes from “tight” and “leaky” epithelia. Journal of Cell Biology. 1973;58:390-400 - 66.
Diamond JM. Twenty-first Bowditch lecture. The epithelial junction: Bridge, gate, and fence. Physiologist. 1977;20:10-18 - 67.
Mandel LJ, Bacallao R, Zampighi G. Uncoupling of the molecular ‘fence’ and paracellular “gate” functions in epithelial tight junctions. Nature. 1993;361:552-555. DOI: 10.1038/361552a0 - 68.
Dragsten PR, Blumenthal R, Handler JS. Membrane asymmetry in epithelia: Is the tight junction a barrier to diffusion in the plasma membrane? Nature. 1981;294:718-722 - 69.
van Meer G, Simons K. The function of tight junctions in maintaining differences in lipid composition between the apical and the basolateral cell surface domains of MDCK cells. The EMBO Journal. 1986;5:1455-1464 - 70.
Cereijido M, Contreras RG, Shoshani L, Flores-Benitez D, Larre I. Tight junction and polarity interaction in the transporting epithelial phenotype. Biochimica et Biophysica Acta. 2008;1778:770-793. DOI: 10.1016/j.bbamem.2007.09.001 - 71.
Laffafian I, Hallett MB. Lipid-protein cargo transfer: A mode of direct cell-to-cell communication for lipids and their associated proteins. Journal of Cellular Physiology. 2007;210:336-342. DOI: 10.1002/jcp.20851 - 72.
Sneyd J, Wetton BT, Charles AC, Sanderson MJ. Intercellular calcium waves mediated by diffusion of inositol trisphosphate: A two-dimensional model. American Journal of Physiology. 1995;268:C1537-C1545 - 73.
Turin L, Béhé P, Plonsky I, Dunina-Barkovskaya A. Hydrophobic ion transfer between membranes of adjacent hepatocytes: A possible probe of tight junction structure. Proceedings of the National Academy of Sciences. 1991;88:9365-9369 - 74.
Grebenkämper K, Galla HJ. Translational diffusion measurements of a fluorescent phospholipid between MDCK-I cells support the lipid model of the tight junctions. Chemistry and Physics of Lipids. 1994;71:133-143 - 75.
Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S. Claudin-1 and -2: Novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. Journal of Cell Biology. 1998;141:1539-1550 - 76.
Haseloff RF, Dithmer S, Winkler L, Wolburg H, Blasig IE. Transmembrane proteins of the tight junctions at the blood-brain barrier: Structural and functional aspects. Seminars in Cell and Developmental Biology. 2015;38:16-25. DOI: 10.1016/j.semcdb.2014.11.004 - 77.
Cereijido M, Contreras RG, Flores-Benítez D, Flores-Maldonado C, Larre I, Ruiz A, et al. New diseases derived or associated with the tight junction. Archives of Medical Research. 2007;38:465-478. DOI: 10.1016/j.arcmed.2007.02.003 - 78.
González-Mariscal L, Betanzos A, Nava P, Jaramillo BE. Tight junction proteins. Progress in Biophysics & Molecular Biology. 2003;81:1-44 - 79.
Tsukita S, Furuse M, Itoh M. Multifunctional strands in tight junctions. Nature Reviews Molecular Cell Biology. 2001;2:285-293. DOI: 10.1038/35067088 - 80.
Anderson JM. Molecular structure of tight junctions and their role in epithelial transport. Physiology. 2001;16:126-130. DOI: 10.1007/BF01870332 - 81.
Cereijido M, Anderson JM. Tight Junctions. CRC Press; 2001. USA - 82.
Gonzalez-Mariscal L. Tight Junctions. Boston, MA: Springer Science & Business Media; 2007. DOI: 10.1007/0-387-36673-3 - 83.
Weber CR, Liang GH, Wang Y, Das S, Shen L, Yu ASL, et al. Claudin-2-dependent paracellular channels are dynamically gated. eLife Sciences. 2016;4:e09906. DOI: 10.7554/eLife.09906 - 84.
Kottra G, Frömter E. Functional properties of the paracellular pathway in some leaky epithelia. Journal of Experimental Biology. 1983;106:217-229 - 85.
Günzel D, Yu ASL. Claudins and the modulation of tight junction permeability. Physiological Reviews. 2013;93:525-569. DOI: 10.1152/physrev.00019.2012 - 86.
Anderson JM, Stevenson BR, Jesaitis LA, Goodenough DA, Mooseker MS. Characterization of ZO-1, a protein component of the tight junction from mouse liver and Madin-Darby canine kidney cells. Journal of Cell Biology. 1988;106:1141-1149 - 87.
Gonzalez-Mariscal L, Betanzos A, Avila-Flores A. MAGUK proteins: Structure and role in the tight junction. Seminars in Cell and Developmental Biology. 2000;11:315-324. DOI: 10.1006/scdb.2000.0178 - 88.
Gonzalez-Mariscal L. Molecular Characterization of the Tight Junction Protein ZO-1 in MDCK Cells*1, *2. Experimental Cell Research. 1999;248:97-109. DOI: 10.1006/excr.1999.4392. - 89.
Fanning AS, Ma TY, Anderson JM. Isolation and functional characterization of the actin binding region in the tight junction protein ZO-1. FASEB Journal. 2002;16:1835-1837. DOI: 10.1096/fj.02-0121fje - 90.
Molecular organization and function of invertebrate occluding junctions. Seminaries in Cell & Developmental Biology. 2014;36:186-193. DOI: 10.1016/j.semcdb.2014.09.009 - 91.
Suzuki H, Ito Y, Yamazaki Y, Mineta K, Uji M, Abe K, et al. The four-transmembrane protein IP39 of Euglena forms strands by a trimeric unit repeat. Nature Communications. 2013;4:1766. DOI: 10.1038/ncomms2731 - 92.
Cereijido M, Robbins ES, Dolan WJ, Rotunno CA, Sabatini DD. Polarized monolayers formed by epithelial cells on a permeable and translucent support. Journal of Cell Biology. 1978;77:853-880 - 93.
Boulpaep EL, Seely JF. Electrophysiology of proximal and distal tubules in the autoperfused dog kidney. American Journal of Physiology. 1971;221:1084-1096 - 94.
Lutz MD, Cardinal JE, Burg MB. Electrical resistance of renal proximal tubule perfused in vitro. American Journal of Physiology. 1973;225:729-734 - 95.
Helman SI, Grantham JJ, Burg MB. Effect of vasopressin on electrical resistance of renal cortical collecting tubules. American Journal of Physiology. 1971;220:1825-1832 - 96.
Rau WS, Frömter E. Electrical properties of the medullary collecting ducts of the golden hamster kidney. II. The transepithelial resistance. Pflügers Archiv. 1974;351:113-131 - 97.
Lavelle JP, Meyers SA, Ruiz WG, Buffington CT, Zeidel ML, Apodaca G. Urothelial pathophysiological changes in feline interstitial cystitis: A human model. American Journal of Physiology. Renal Physiology. 2000;278:F540-F553 - 98.
Lewis SA, Eaton DC, Clausen CH, Diamond JM. Nystatin as a probe for investigating the electrical properties of a tight epithelium. The Journal of General Physiology. 1977;70:427-440 - 99.
Furuse M, Furuse K, Sasaki H, Tsukita S. Conversion of zonulae occludentes from tight to leaky strand type by introducing claudin-2 into Madin-Darby canine kidney I cells. Journal of Cell Biology. 2001;153:263-272 - 100.
Amasheh S, Meiri N, Gitter AH, Schöneberg T, Mankertz J, Schulzke JD, et al. Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells. Journal of Cell Science. 2002;115:4969-4976 - 101.
Rosenthal R, Milatz S, Krug SM, Oelrich B, Schulzke JD, Amasheh S, et al., Claudin-2, a component of the tight junction, forms a paracellular water channel. Journal of Cell Science. 2010;123:1913-1921. DOI: 10.1242/jcs.060665 - 102.
Gonzalez-Mariscal L, Del CarmenNamorado M, Martin D, Sierra G, Reyes JL. The tight junction proteins claudin-7 and -8 display a different subcellular localization at Henle's loops and collecting ducts of rabbit kidney. Nephrology, Dialysis, Transplantation. 2006;21:2391-2398. DOI: 10.1093/ndt/gfl255 - 103.
Kiuchi-Saishin Y, Gotoh S, Furuse M, Takasuga A, Tano Y, Tsukita S. Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments. Journal of the American Society of Nephrology. 2002;13:875-886 - 104.
Reyes JL, Lamas M, Martin D, Namorado MD, Islas S, Luna J, et al. The renal segmental distribution of claudins changes with development. Kidney International. 2002;62:476-487. DOI: 10.1046/j.1523-1755.2002.00479.x - 105.
Muto S, Hata M, Taniguchi J, Tsuruoka S, Moriwaki K, Saitou M, et al., Claudin-2-deficient mice are defective in the leaky and cation-selective paracellular permeability properties of renal proximal tubules. Proceedings of the National academy of Sciences of the United States of America. 2010;107:8011-8016. DOI: 10.1073/pnas.0912901107 - 106.
Colegio OR, Van Itallie C, Rahner C, Anderson JM. Claudin extracellular domains determine paracellular charge selectivity and resistance but not tight junction fibril architecture. American Journal of Physiology. Cell Physiology. 2003;284:C1346-C1354. DOI: 10.1152/ajpcell.00547.2002 - 107.
Colegio OR, Van Itallie CM, McCrea HJ, Rahner C, Anderson JM. Claudins create charge-selective channels in the paracellular pathway between epithelial cells. American Journal of Physiology. Cell Physiology. 2002;283:C142-C147. DOI: 10.1152/ajpcell.00038.2002 - 108.
Morita K, Furuse M, Fujimoto K, Tsukita S. Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. Proceedings of the National Academy of Sciences. 1999;96:511-516 - 109.
Gallardo JM, Hernández JM, Contreras RG, Flores-Maldonado C, González-Mariscal L, Cereijido M. Tight junctions are sensitive to peptides eliminated in the urine. Journal of Membrane Biology. 2002;188:33-42. DOI: 10.1007/s00232-001-0170-6 - 110.
Flores-Benitez D, Ruiz-Cabrera A, Flores-Maldonado C, Shoshani L, Cereijido M, Contreras RG. Control of tight junctional sealing: Role of epidermal growth factor. American Journal of Physiology. Renal Physiology. 2007;292:F828-F836. DOI: 10.1152/ajprenal.00369.2006 - 111.
Mullin JM, Laughlin KV, Ginanni N, Marano CW, Clarke HM, Peralta Soler A. Increased tight junction permeability can result from protein kinase C activation/translocation and act as a tumor promotional event in epithelial cancers. Annals of the New York Academy of Sciences. 2000;915:231-236 - 112.
Singh AB, Harris RC. Epidermal growth factor receptor activation differentially regulates claudin expression and enhances transepithelial resistance in Madin-Darby canine kidney cells. Journal of Biological Chemistry. 2004;279:3543-3552. DOI: 10.1074/jbc.M308682200 - 113.
Ikari A, Takiguchi A, Atomi K, Sugatani J. Epidermal growth factor increases clathrin-dependent endocytosis and degradation of claudin-2 protein in MDCK II cells. Journal of Cellular Physiology. 2011;226:2448-2456. DOI: 10.1002/jcp.22590 - 114.
Garcia-Hernandez V, Flores-Maldonado C, Rincon-Heredia R, Verdejo-Torres O, Bonilla-Delgado J, Meneses-Morales I, et al. EGF regulates claudin-2 and -4 expression through Src and STAT3 in MDCK cells. Journal of Cellular Physiology. 2015;230:105-115. DOI: 10.1002/jcp.24687 - 115.
Singh AB, Dhawan P. Claudins and cancer: Fall of the soldiers entrusted to protect the gate and keep the barrier intact. Seminars in Cell and Developmental Biology. 2015;42:58-65. DOI: 10.1016/j.semcdb.2015.05.001 - 116.
Ikari A, Atomi K, Takiguchi A, Yamazaki Y, Miwa M, Sugatani J. Epidermal growth factor increases claudin-4 expression mediated by Sp1 elevation in MDCK cells. Biochemical and Biophysical Research Communications. 2009;384:306-310. DOI: 10.1016/j.bbrc.2009.04.120 - 117.
Ikari A, Atomi K, Takiguchi A, Yamazaki Y, Hayashi H, Hirakawa J, et al. Enhancement of cell-cell contact by claudin-4 in renal epithelial Madin-Darby canine kidney cells. Journal of Cellular Biochemistry. 2012;113:499-507. DOI: 10.1002/jcb.23373 - 118.
Flores-Benitez D, Rincon-Heredia R, Razgado LF, Larre I, Cereijido M, Contreras RG. Control of tight junctional sealing: Roles of epidermal growth factor and prostaglandin E2. American Journal of Physiology. Cell Physiology. 2009;297:C611-C620. DOI: 10.1152/ajpcell.00622.2008 - 119.
Lu R, Johnson DL, Stewart L, Waite K, Elliott D, Wilson JM. Rab14 regulation of claudin-2 trafficking modulates epithelial permeability and lumen morphogenesis. Molecular Biology of the Cell. 2014;25:1744-1754. DOI: 10.1091/mbc.E13-12-0724 - 120.
Nighot PK, Hu CA, Ma TY. Autophagy enhances intestinal epithelial tight junction barrier function by targeting claudin-2 protein degradation. Journal of Biological Chemistry. 2015;290:7234-7246. DOI: 10.1074/jbc.M114.597492 - 121.
Yang Y, Li W, Sun Y, Han F, Hu CA, Wu Z. Amino acid deprivation disrupts barrier function and induces protective autophagy in intestinal porcine epithelial cells. Amino Acids. 2015;47:2177-2184. DOI: 10.1007/s00726-014-1844-6 - 122.
Zhou Y, Zheng B, Ye L, Zhang H, Zhu S, Zheng X, et al. Retinoic acid prevents disruption of blood-spinal cord barrier by inducing autophagic flux after spinal cord injury. Neurochemical Research. 2016;41:813-825. DOI: 10.1007/s11064-015-1756-1 - 123.
Withering W. An Account of the Foxglove, and Some of Its Medical Uses, 1st ed. Printed by N. Swinney for GGJ and J. Robinson, Paternoster-Row. London; 1785 - 124.
Schatzmann HJ. Herzglykoside als Hemmstoffe für den aktiven Kalium- und Natriumtransport durch die Erythrocytenmembran. Helvetica Physiologica et Pharmacologica Acta. 1953;11:346-354 - 125.
Bauer N, Müller-Ehmsen J, Krämer U, Hambarchian N, Zobel C, Schwinger RH, Neu H, Kirch U, Grünbaum EG, Schoner W. Ouabain-like compound changes rapidly on physical exercise in humans and dogs: Effects of beta-blockade and angiotensin-converting enzyme inhibition. Hypertension. 2005;45:1024-1028. DOI: 10.1161/01.HYP.0000165024.47728.f7 - 126.
Schneider R, Wray V, Nimtz M, Lehmann WD, Kirch U, Antolovic R, et al. Bovine adrenals contain, in addition to ouabain, a second inhibitor of the sodium pump. Journal of Biological Chemistry. 1998;273:784-792 - 127.
Schoner W, Bauer N, Müller‐Ehmsen J, KrÄmer U, Hambarchian N, Schwinger R, et al. Ouabain as a mammalian hormone. Annals of the New York Academy of Sciences. 2003;986:678-684 - 128.
Schoner W, Scheiner-Bobis G. Endogenous cardiac glycosides: Hormones using the sodium pump as signal transducer. Seminars in Nephrology. 2005;25:343-351. DOI: 10.1016/j.semnephrol.2005.03.010 - 129.
Moreth K, Kuske R, Renner D, Schoner W. Blood pressure in essential hypertension correlates with the concentration of a circulating inhibitor of the sodium pump. Klinische Wochenschrift. 1986;64:239-244. DOI: 10.1007/BF01711656 - 130.
Fedorova OV, Shapiro JI, Bagrov AY. Endogenous cardiotonic steroids and salt-sensitive hypertension. Biochimica Et Biophysica Acta (BBA)—Molecular Basis of Disease. 2010;1802:1230-1236. DOI: 10.1016/j.bbadis.2010.03.011 - 131.
Nesher M, Shpolansky U, Viola N, Dvela M, Buzaglo N, Ben‐Ami HC, et al. Ouabain attenuates cardiotoxicity induced by other cardiac steroids. British Journal of Pharmacology. 2010;160:346-354. DOI: 10.1111/j.1476-5381.2010.00701.x - 132.
Koltsova SV, Trushina Y, Haloui M, Akimova OA, Tremblay J, Hamet P, et al. Ubiquitous [Na+]i/[K+]i-sensitive transcriptome in mammalian cells: Evidence for Ca(2+)i-independent excitation-transcription coupling. PLoS One. 2012;7:e38032. DOI: 10.1371/journal.pone.0038032 - 133.
Wang H, Haas M, Liang M, Cai T, Tian J, Li S, et al. Ouabain assembles signaling cascades through the caveolar Na+/K+-ATPase. Journal of Biological Chemistry. 2004;279:17250-17259. DOI: 10.1074/jbc.M313239200 - 134.
Aizman O, Uhlén P, Lal M, Brismar H, Aperia A. Ouabain, a steroid hormone that signals with slow calcium oscillations. Proceedings of the National Academy of Sciences. 2001;98:13420-13424. DOI: 10.1073/pnas.221315298 - 135.
Zhang S, Malmersjö S, Li J, Ando H, Aizman O, Uhlén P, et al. Distinct role of the N-terminal tail of the Na,K-ATPase catalytic subunit as a signal transducer. Journal of Biological Chemistry. 2006;281:21954-21962. DOI: 10.1074/jbc.M601578200 - 136.
Akimova OA, Hamet P, Orlov SN. [Na+]i/[K+]i-independent death of ouabain-treated renal epithelial cells is not mediated by Na+,K+-ATPase internalization and de novo gene expression. Pflügers Archiv. 2008;455:711-719. DOI: 10.1007/s00424-007-0283-6 - 137.
Contreras RG, Flores-Maldonado C, Lazaro A, Shoshani L, Flores-Benitez D, Larre I, et al. Ouabain binding to Na+,K+-ATPase relaxes cell attachment and sends a specific signal (NACos) to the nucleus. Journal of Membrane Biology. 2004;198:147-158. DOI: 10.1007/s00232-004-0670-2 - 138.
Liang M, Cai T, Tian J, Qu W, Xie ZJ. Functional characterization of Src-interacting Na/K-ATPase using RNA interference assay. Journal of Biological Chemistry. 2006;281:19709-19719. DOI: 10.1074/jbc.M512240200 - 139.
Larré I, Lazaro A, Contreras RG, Balda MS, Matter K, Flores-Maldonado C, et al. Ouabain modulates epithelial cell tight junction. Proceedings of the National academy of Sciences of the United States of America. 2010;107:11387-11392. DOI: 10.1073/pnas.1000500107 - 140.
Contreras RG, Shoshani L, Flores-Maldonado C, Lázaro A, Cereijido M. Relationship between Na(+),K(+)-ATPase and cell attachment. Journal of Cell Science. 1999; 112 (Pt 23):4223-4232 - 141.
Rincon-Heredia R, Flores-Benitez D, Flores-Maldonado C, Bonilla-Delgado J, García-Hernández V, Verdejo-Torres O, et al. Ouabain induces endocytosis and degradation of tight junction proteins through ERK1/2-dependent pathways. Experimental Cell Research. 2014;320:108-118. DOI: 10.1016/j.yexcr.2013.10.008 - 142.
Akimova OA, Tverskoi AM, Smolyaninova LV, Mongin AA, Lopina OD, La J, et al. Critical role of the α1-Na+, K+-ATPase subunit in insensitivity of rodent cells to cytotoxic action of ouabain. Apoptosis. 2015;20:1200-1210. DOI: 10.1007/s10495-015-1144-y - 143.
Akimova OA, Tremblay J, Van Huysse JW, Hamet P, Orlov SN. Cardiotonic steroid-resistant alpha1-Na+,K+-ATPase rescues renal epithelial cells from the cytotoxic action of ouabain: Evidence for a Nai+,Ki+-independent mechanism. Apoptosis. 2010;15:55-62. DOI: 10.1007/s10495-009-0429-4 - 144.
Contreras RG, Flores-Beni TD, Flores-Maldonado C, Larre I, Shoshani L, Cereijido M. Na+,K+-ATPase and hormone ouabain:new roles for an old enzyme and an old inhibitor. Cellular and Molecular Biology (Noisy-le-Grand, France). 2006;52:31-40 - 145.
Hou J, Rajagopal M, Yu ASL. Claudins and the kidney. Annual Review of Physiology. 2013;75:479-501. DOI: 10.1146/annurev-physiol-030212-183705 - 146.
Arteaga ME, Hunziker W, Teo AS, Hillmer AM, Mutchinick OM. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: Variable phenotypic expression in three affected sisters from Mexican ancestry. Renal Failure. 2015;37:180-183. DOI: 10.3109/0886022X.2014.977141 - 147.
Sharma S, Place E, Lord K, Leroy BP, Falk MJ, Pradhan M. Claudin 19-based familial hypomagnesemia with hypercalciuria and nephrocalcinosis in a sibling pair. Clinical Nephrology. 2016;85:346-352. DOI: 10.5414/CN108783 - 148.
Hou J, Renigunta A, Konrad M, Gomes AS, Schneeberger EE, Paul DL, et al. Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex. Journal of Clinical Investigation. 2008;118:619-628. DOI: 10.1172/JCI33970 - 149.
Hou J, Paul DL, Goodenough DA. Paracellin-1 and the modulation of ion selectivity of tight junctions. Journal of Cell Science. 2005;118:5109-5118. DOI: 10.1242/jcs.02631 - 150.
Gong Y, Renigunta V, Zhou Y, Sunq A, Wang J, Yang J, et al. Biochemical and biophysical analyses of tight junction permeability made of claudin-16 and claudin-19 dimerization. Molecular Biology of the Cell. 2015;26(24):4333-4346. DOI: 10.1091/mbc.E15-06-0422 - 151.
Kausalya PJ, Amasheh S, Günzel D, Wurps H, Müller D, Fromm M, et al. Disease-associated mutations affect intracellular traffic and paracellular Mg2+ transport function of Claudin-16. Journal of Clinical Investigation. 2006;116:878-891. DOI: 10.1172/JCI26323 - 152.
Müller D, Kausalya PJ, Meij IC, Hunziker W. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: Blocking endocytosis restores surface expression of a novel Claudin-16 mutant that lacks the entire C-terminal cytosolic tail. Human Molecular Genetics. 2006;15:1049-1058. DOI: 10.1093/hmg/ddl020 - 153.
Müller D, Kausalya PJ, Claverie-Martin F, Meij IC, Eggert P, Garcia-Nieto V, et al. A novel claudin 16 mutation associated with childhood hypercalciuria abolishes binding to ZO-1 and results in lysosomal mistargeting. The American Journal of Human Genetics. 2003;73:1293-1301. DOI: 10.1086/380418 - 154.
Ikari A, Matsumoto S, Harada H, Takagi K, Degawa M, Takahashi T, et al. Dysfunction of paracellin-1 by dephosphorylation in Dahl salt-sensitive hypertensive rats. Journal of Physiological Sciences. 2006;56:379-383. DOI: 10.2170/physiolsci.SC008906 - 155.
Cong X, Zhang Y, Li J, Mei M, Ding C, Xiang RL, et al. Claudin-4 is required for modulation of paracellular permeability by muscarinic acetylcholine receptor in epithelial cells. Journal of Cell Science. 2015;128:2271-2286. DOI: 10.1242/jcs.165878 - 156.
Mandai K, Nakanishi H, Satoh A, Obaishi H, Wada M, Nishioka H, et al. Afadin: A novel actin filament-binding protein with one PDZ domain localized at cadherin-based cell-to-cell adherens junction. Journal of Cell Biology. 1997;139:517-528 - 157.
Sakisaka T, Ikeda W, Ogita H, Fujita N, Takai Y. The roles of nectins in cell adhesions: Cooperation with other cell adhesion molecules and growth factor receptors. Current Opinion in Cell Biology. 2007;19:593-602. DOI: 10.1016/j.ceb.2007.09.007 - 158.
Kemler R, Ozawa M. Uvomorulin-catenin complex: Cytoplasmic anchorage of a Ca2+-dependent cell adhesion molecule. Bioessays. 1989;11:88-91. DOI: 10.1002/bies.950110403 - 159.
Hirano S, Takeichi M. Cadherins in brain morphogenesis and wiring. Physiological Reviews. 2012;92:597-634. DOI: 10.1152/physrev.00014.2011 - 160.
Nose A, Nagafuchi A, Takeichi M. Expressed recombinant cadherins mediate cell sorting in model systems. Cell. 1988;54:993-1001 - 161.
Takeichi M. Cadherin cell adhesion receptors as a morphogenetic regulator. Science. 1991;251:1451-1455 - 162.
Pokutta S, Weis WI. Structure and mechanism of cadherins and catenins in cell-cell contacts. Annual Review of Cell and Developmental Biology. 2007;23:237-261. DOI: 10.1146/annurev.cellbio.22.010305.104241 - 163.
Niessen CM, Gottardi CJ. Molecular components of the adherens junction. Biochimica et Biophysica Acta. 2008;1778:562-571. DOI: 10.1016/j.bbamem.2007.12.015 - 164.
Gumbiner BM. Regulation of cadherin-mediated adhesion in morphogenesis. Nature Reviews Molecular Cell Biology. 2005;6:622-634. DOI: 10.1038/nrm1699 - 165.
Abedin M, King N. The premetazoan ancestry of cadherins. Science. 2008;319:946-948. DOI: 10.1126/science.1151084 - 166.
Nanes BA, Chiasson-MacKenzie C, Lowery AM, Ishiyama N, Faundez V, Ikura M, et al. p120-catenin binding masks an endocytic signal conserved in classical cadherins. Journal of Cell Biology. 2012;199:365-380. DOI: 10.1083/jcb.201205029 - 167.
Anastasiadis PZ, Reynolds AB. The p120 catenin family: Complex roles in adhesion, signaling and cancer. Journal of Cell Science. 2000;113(Pt 8):1319-1334. - 168.
Fujita Y, Krause G, Scheffner M, Zechner D, Leddy HEM, Behrens J, et al. Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nature Cell Biology. 2002;4:222-231. DOI: 10.1038/ncb758 - 169.
Petherick KJ, Williams AC, Lane JD, Ordóñez-Morán P, Huelsken J, Collard TJ, et al. Autolysosomal β-catenin degradation regulates Wnt-autophagy-p62 crosstalk. The EMBO Journal. 2013;32:1903-1916. DOI: 10.1038/emboj.2013.123 - 170.
Gugnoni M, Sancisi V, Gandolfi G, Manzotti G, Ragazzi M, Giordano D, et al. Cadherin-6 promotes EMT and cancer metastasis by restraining autophagy. Oncogene. 2017;36:667-677. DOI: 10.1038/onc.2016.237 - 171.
Pang M, Wang H, Rao P, Zhao Y, Xie J, Cao Q, et al. Autophagy links β-catenin and Smad signaling to promote epithelial-mesenchymal transition via upregulation of integrin linked kinase. International Journal of Biochemistry and Cell Biology. 2016;76:123-134. DOI: 10.1016/j.biocel.2016.05.010 - 172.
Goodenough DA, Goliger JA, Paul DL. Connexins, connexons, and intercellular communication. Annual Review of Biochemistry. 1996;65:475-502. DOI: 10.1146/annurev.bi.65.070196.002355 - 173.
Goodenough DA, Paul DL. Beyond the gap: Functions of unpaired connexon channels. Nature Reviews Molecular Cell Biology. 2003;4:285-294. DOI: 10.1038/nrm1072 - 174.
Hervé JC, Derangeon M. Gap-junction-mediated cell-to-cell communication. Cell and Tissue Research. 2013;352:21-31. DOI: 10.1007/s00441-012-1485-6 - 175.
Prochnow N, Dermietzel R. Connexons and cell adhesion: A romantic phase. Histochemistry and Cell Biology. 2008;130:71-77. DOI: 10.1007/s00418-008-0434-7 - 176.
Hervé JC, Bourmeyster N, Sarrouilhe D. Diversity in protein-protein interactions of connexins: Emerging roles. Biochimica et Biophysica Acta. 2004;1662:22-41. DOI: 10.1016/j.bbamem.2003.10.022 - 177.
Singh D, Solan JL, Taffet SM, Javier R, Lampe PD. Connexin 43 interacts with zona occludens-1 and -2 proteins in a cell cycle stage-specific manner. Journal of Biological Chemistry. 2005;280:30416-30421. DOI: 10.1074/jbc.M506799200 - 178.
Green KJ, Jones JC. Desmosomes and hemidesmosomes: Structure and function of molecular components. FASEB Journal. 1996;10:871-881 - 179.
Nekrasova O, Green KJ. Desmosome assembly and dynamics. Trends in Cell Biology. 2013;23:537-546. DOI: 10.1016/j.tcb.2013.06.004 - 180.
Getsios S, Huen AC, Green KJ. Working out the strength and flexibility of desmosomes. Nature Reviews Molecular Cell Biology. 2004;5:271-281. DOI: 10.1038/nrm1356 - 181.
Wallis S, Lloyd S, Wise I, Ireland G, Fleming TP, Garrod D. The alpha isoform of protein kinase C is involved in signaling the response of desmosomes to wounding in cultured epithelial cells. Molecular Biology of the Cell. 2000;11:1077-1092 - 182.
Garrod DR, Berika MY, Bardsley WF, Holmes D, Tabernero L. Hyper-adhesion in desmosomes: Its regulation in wound healing and possible relationship to cadherin crystal structure. Journal of Cell Science. 2005;118:5743-5754. DOI: 10.1242/jcs.02700 - 183.
Goodenough DA, Gilula NB. The splitting of hepatocyte gap junctions and zonulae occludentes with hypertonic disaccharides. Journal of Cell Biology. 1974;61:575-590 - 184.
Ghoshroy S, Goodenough DA, Sosinsky GE. Preparation, characterization, and structure of half gap junctional layers split with urea and EGTA. Journal of Membrane Biology. 1995;146:15-28 - 185.
Berthoud VM, Minogue PJ, Laing JG, Beyer EC. Pathways for degradation of connexins and gap junctions. Cardiovascular Research. 2004;62:256-267. DOI: 10.1016/j.cardiores.2003.12.021 - 186.
Bjorkman N. A study of the ultrastructure of the granulosa cells of the rat ovary. Acta Anatomica (Basel). 1962;51:125-147 - 187.
Carette D, Gilleron J, Denizot JP, Grant K, Pointis G, Segretain D. New cellular mechanisms of gap junction degradation and recycling. Biology of the Cell. 2015;107:218-231. DOI: 10.1111/boc.201400048 - 188.
Zou H, Zhuo L, Han T, Hu D, Yang X, Wang Y, et al. Autophagy and gap junctional intercellular communication inhibition are involved in cadmium-induced apoptosis in rat liver cells. Biochemical and Biophysical Research Communications. 2015;459:713-719. DOI: 10.1016/j.bbrc.2015.03.027 - 189.
Falk MM, Kells RM, Berthoud VM. Degradation of connexins and gap junctions. FEBS Letters. 2014;588(8):1221-1229. DOI: 10.1016/j.febslet.2014.01.031 - 190.
Bejarano E, Girao H, Yuste A, Patel B, Marques C, Spray DC, et al. Autophagy modulates dynamics of connexins at the plasma membrane in a ubiquitin-dependent manner. Molecular Biology of the Cell. 2012;23:2156-2169. DOI: 10.1091/mbc.E11-10-0844 - 191.
Garrod D, Tabernero L. Hyper-adhesion: A unique property of desmosomes. Cell Communication & Adhesion. 2014;21:249-256. DOI: 10.3109/15419061.2014.930133 - 192.
Allen TD, Potten CS. Desmosomal form, fate, and function in mammalian epidermis. Journal of Ultrastructure Research. 1975;51:94-105 - 193.
McHarg S, Hopkins G, Lim L, Garrod D. Down-regulation of desmosomes in cultured cells: The roles of PKC, microtubules and lysosomal/proteasomal degradation. PLoS One. 2014;9:e108570. DOI: 10.1371/journal.pone.0108570 - 194.
Calkins CC, Setzer SV, Jennings JM, Summers S, Tsunoda K, Amagai M, et al. Desmoglein endocytosis and desmosome disassembly are coordinated responses to pemphigus autoantibodies. Journal of Biological Chemistry. 2006;281:7623-7634. DOI: 10.1074/jbc.M512447200 - 195.
Barczyk M, Carracedo S, Gullberg D. Integrins. Cell and Tissue Research. 2010;339:269-280. DOI: 10.1007/s00441-009-0834-6 - 196.
Hynes RO. Integrins: Bidirectional, allosteric signaling machines. Cell. 2002;110:673-687 - 197.
Oommen S, Francois M, Kawasaki M, Murrell M, Kawasaki K, Porntaveetus T, et al. Cytoplasmic plaque formation in hemidesmosome development is dependent on SoxF transcription factor function. PLoS One. 2012;7:e43857. DOI: 10.1371/journal.pone.0043857 - 198.
Burridge K, Guilluy C. Focal adhesions, stress fibers and mechanical tension. Experimental Cell Research. 2016;343:14-20. DOI: 10.1016/j.yexcr.2015.10.029 - 199.
Wehrle-Haller B. Structure and function of focal adhesions. Current Opinion in Cell Biology. 2012;24:116-124. DOI: 10.1016/j.ceb.2011.11.001 - 200.
Paluch EK, Aspalter IM, Sixt M. Focal adhesion-independent cell migration. Annual Review of Cell and Developmental Biology. 2016;32:469-490. DOI: 10.1146/annurev-cellbio-111315-125341 - 201.
Tuloup-Minguez V, Hamaï A, Greffard A, Nicolas V, Codogno P, Botti J. Autophagy modulates cell migration and β1 integrin membrane recycling. Cell Cycle. 2013;12:3317-3328. DOI: 10.4161/cc.26298 - 202.
De Franceschi N, Hamidi H, Alanko J, Sahgal P, Ivaska J. Integrin traffic—the update. Journal of Cell Science. 2015;128:839-852. DOI: 10.1242/jcs.161653 - 203.
Vlahakis A, Jayanta D. The interconnections between autophagy and integrin-mediated cell adhesion. Journal of Molecular Biology. 2016:1-16. DOI: 10.1016/j.jmb.2016.11.027 - 204.
Kenific CM, Torsen W, Jayanta D. Autophagy in adhesion and migration. Journal of Cell Science. 2016;129:3685-3693. DOI: 10.1242/jcs.188490