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CD148 tyrosine phosphatase promotes cadherin cell adhesion.
Takahashi K, Matafonov A, Sumarriva K, Ito H, Lauhan C, Zemel D, Tsuboi N, Chen J, Reynolds A, Takahashi T
(2014) PLoS One 9: e112753
MeSH Terms: Cadherins, Cell Adhesion, Cell Line, Drosophila Proteins, Humans, Phosphorylation, Receptor-Like Protein Tyrosine Phosphatases, Class 3, Tyrosine, beta Catenin, cdc42 GTP-Binding Protein, rac GTP-Binding Proteins, rhoA GTP-Binding Protein
Show Abstract · Added February 12, 2015
CD148 is a transmembrane tyrosine phosphatase that is expressed at cell junctions. Recent studies have shown that CD148 associates with the cadherin/catenin complex and p120 catenin (p120) may serve as a substrate. However, the role of CD148 in cadherin cell-cell adhesion remains unknown. Therefore, here we addressed this issue using a series of stable cells and cell-based assays. Wild-type (WT) and catalytically inactive (CS) CD148 were introduced to A431D (lacking classical cadherins), A431D/E-cadherin WT (expressing wild-type E-cadherin), and A431D/E-cadherin 764AAA (expressing p120-uncoupled E-cadherin mutant) cells. The effects of CD148 in cadherin adhesion were assessed by Ca2+ switch and cell aggregation assays. Phosphorylation of E-cadherin/catenin complex and Rho family GTPase activities were also examined. Although CD148 introduction did not alter the expression levels and complex formation of E-cadherin, p120, and β-catenin, CD148 WT, but not CS, promoted cadherin contacts and strengthened cell-cell adhesion in A431D/E-cadherin WT cells. This effect was accompanied by an increase in Rac1, but not RhoA and Cdc42, activity and largely diminished by Rac1 inhibition. Further, we demonstrate that CD148 reduces the tyrosine phosphorylation of p120 and β-catenin; causes the dephosphorylation of Y529 suppressive tyrosine residue in Src, a well-known CD148 site, increasing Src activity and enhancing the phosphorylation of Y228 (a Src kinase site) in p120, in E-cadherin contacts. Consistent with these findings, CD148 dephosphorylated both p120 and β-catenin in vitro. The shRNA-mediated CD148 knockdown in A431 cells showed opposite effects. CD148 showed no effects in A431D and A431D/E-cadherin 764AAA cells. In aggregate, these findings provide the first evidence that CD148 promotes E-cadherin adhesion by regulating Rac1 activity concomitant with modulation of p120, β-catenin, and Src tyrosine phosphorylation. This effect requires E-cadherin and p120 association.
1 Communities
2 Members
0 Resources
12 MeSH Terms
Concerted loss of TGFβ-mediated proliferation control and E-cadherin disrupts epithelial homeostasis and causes oral squamous cell carcinoma.
Andl T, Le Bras GF, Richards NF, Allison GL, Loomans HA, Washington MK, Revetta F, Lee RK, Taylor C, Moses HL, Andl CD
(2014) Carcinogenesis 35: 2602-10
MeSH Terms: Animals, Antigens, CD, Cadherins, Carcinogenesis, Carcinoma, Squamous Cell, Cell Proliferation, Cyclin D1, Epithelial Cells, Homeostasis, Humans, Mice, Mouth Neoplasms, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Signal Transduction, Tamoxifen
Show Abstract · Added December 3, 2014
Although the etiology of squamous cell carcinomas of the oral mucosa is well understood, the cellular origin and the exact molecular mechanisms leading to their formation are not. Previously, we observed the coordinated loss of E-cadherin (CDH1) and transforming growth factor beta receptor II (TGFBR2) in esophageal squamous tumors. To investigate if the coordinated loss of Cdh1 and Tgfbr2 is sufficient to induce tumorigenesis in vivo, we developed two mouse models targeting ablation of both genes constitutively or inducibly in the oral-esophageal epithelium. We show that the loss of both Cdh1 and Tgfbr2 in both models is sufficient to induce squamous cell carcinomas with animals succumbing to the invasive disease by 18 months of age. Advanced tumors have the ability to invade regional lymph nodes and to establish distant pulmonary metastasis. The mouse tumors showed molecular characteristics of human tumors such as overexpression of Cyclin D1. We addressed the question whether TGFβ signaling may target known stem cell markers and thereby influence tumorigenesis. From our mouse and human models, we conclude that TGFβ signaling regulates key aspects of stemness and quiescence in vitro and in vivo. This provides a new explanation for the importance of TGFβ in mucosal homeostasis.
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
2 Communities
3 Members
0 Resources
17 MeSH Terms
Spatial control of Cdc42 signalling by a GM130-RasGRF complex regulates polarity and tumorigenesis.
Baschieri F, Confalonieri S, Bertalot G, Di Fiore PP, Dietmaier W, Leist M, Crespo P, Macara IG, Farhan H
(2014) Nat Commun 5: 4839
MeSH Terms: Antigens, CD, Autoantigens, Cadherins, Carcinogenesis, Cell Line, Tumor, Cell Polarity, Gene Expression Regulation, Neoplastic, Gene Silencing, Humans, MAP Kinase Signaling System, MCF-7 Cells, Membrane Proteins, Mitogen-Activated Protein Kinase 3, Rho Guanine Nucleotide Exchange Factors, Signal Transduction, cdc42 GTP-Binding Protein, ras Guanine Nucleotide Exchange Factors, ras-GRF1
Show Abstract · Added April 10, 2018
The small GTPase Cdc42 is a key regulator of polarity, but little is known in mammals about its spatial regulation and the relevance of spatial Cdc42 pools for polarity. Here we report the identification of a GM130-RasGRF complex as a regulator of Cdc42 at the Golgi. Silencing GM130 results in RasGRF-dependent inhibition of the Golgi pool of Cdc42, but does not affect Cdc42 at the cell surface. Furthermore, active Cdc42 at the Golgi is important to sustain asymmetric front-rear Cdc42-GTP distribution in directionally migrating cells. Concurrent to Cdc42 inhibition, silencing GM130 also results in RasGRF-dependent Ras-ERK pathway activation. Moreover, depletion of GM130 is sufficient to induce E-cadherin downregulation, indicative of a loss in cell polarity and epithelial identity. Accordingly, GM130 expression is frequently lost in colorectal and breast cancer patients. These findings establish a previously unrecognized role for a GM130-RasGRF-Cdc42 connection in regulating polarity and tumorigenesis.
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1 Members
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18 MeSH Terms
Epithelial homeostasis.
Macara IG, Guyer R, Richardson G, Huo Y, Ahmed SM
(2014) Curr Biol 24: R815-25
MeSH Terms: Cadherins, Cell Adhesion, Cell Membrane, Diffusion, Epithelial Cells, Epithelium, Homeostasis, Humans, Tight Junctions
Show Abstract · Added April 10, 2018
Epithelia form intelligent, dynamic barriers between the external environment and an organism's interior. Intercellular cadherin-based adhesions adapt and respond to mechanical forces and cell density, while tight junctions flexibly control diffusion both within the plasma membrane and between adjacent cells. Epithelial integrity and homeostasis are of central importance to survival, and mechanisms have evolved to ensure these processes are maintained during growth and in response to damage. For instance, cell competition surveys the fitness of cells within epithelia and removes the less fit; extrusion or delamination can remove apoptotic or defective cells from the epithelial sheet and can restore homeostasis when an epithelial layer becomes too crowded; spindle orientation ensures two-dimensional growth in simple epithelia and controls stratification in complex epithelia; and transition to a mesenchymal phenotype enables active escape from an epithelial layer. This review will discuss these various mechanisms and consider how they are subverted in disease.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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1 Members
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MeSH Terms
Effects of phonation time and magnitude dose on vocal fold epithelial genes, barrier integrity, and function.
Kojima T, Valenzuela CV, Novaleski CK, Van Deusen M, Mitchell JR, Garrett CG, Sivasankar MP, Rousseau B
(2014) Laryngoscope 124: 2770-8
MeSH Terms: Animals, Cadherins, Cyclooxygenase 2, Disease Models, Animal, Follow-Up Studies, Gene Expression Regulation, Interleukin-1beta, Microscopy, Electron, Scanning, Occludin, Phonation, RNA, Messenger, Rabbits, Real-Time Polymerase Chain Reaction, Time Factors, Transforming Growth Factor beta1, Vocal Cords, beta Catenin
Show Abstract · Added February 12, 2015
OBJECTIVES/HYPOTHESIS - To investigate the effects of increasing time and magnitude doses of vibration exposure on transcription of the vocal fold's junctional proteins, structural alterations, and functional tissue outcomes.
STUDY DESIGN - Animal study.
METHODS - 100 New Zealand White breeder rabbits were studied. Dependent variables were measured in response to increasing time doses (30, 60, or 120 minutes) and magnitude doses (control, modal intensity, and raised intensity) of vibration exposure. Messenger RNA expression of occludin, zonula occluden-1 (ZO-1), E-cadherin, β-catenin, interleukin 1β, cyclooxygenase-2, transforming growth factor β-1, and fibronectin were measured. Tissue structural alterations were assessed using transmission electron microscopy (TEM). Transepithelial resistance was used to measure functional tissue outcomes.
RESULTS - Occludin gene expression was downregulated in vocal folds exposed to 120-minute time doses of raised-intensity phonation, relative to control, and modal-intensity phonation. ZO-1 gene expression was upregulated following a 120-minute time dose of modal-intensity phonation, compared to control, and downregulated after a 120-minute time dose of raised-intensity phonation, compared to modal-intensity phonation. E-cadherin gene expression was downregulated after a 120-minute time dose of raised-intensity phonation, compared to control and modal-intensity phonation. TEM revealed extensive desquamation of the stratified squamous epithelial cells with increasing time and magnitude doses of vibration exposure. A general observation of lower transepithelial resistance measures was made in tissues exposed to raised-intensity phonation compared to all other groups.
CONCLUSIONS - This study provides evidence of vocal fold tissue responses to varying time and magnitude doses of vibration exposure.
LEVEL OF EVIDENCE - NA.
© 2014 The American Laryngological, Rhinological and Otological Society, Inc.
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1 Members
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17 MeSH Terms
DIPA-family coiled-coils bind conserved isoform-specific head domain of p120-catenin family: potential roles in hydrocephalus and heterotopia.
Markham NO, Doll CA, Dohn MR, Miller RK, Yu H, Coffey RJ, McCrea PD, Gamse JT, Reynolds AB
(2014) Mol Biol Cell 25: 2592-603
MeSH Terms: Adherens Junctions, Amino Acid Sequence, Animals, Cadherins, Catenins, Cell Line, Tumor, Conserved Sequence, Dogs, Gene Knockdown Techniques, HEK293 Cells, Humans, Hydrocephalus, Madin Darby Canine Kidney Cells, Molecular Sequence Data, Neural Tube Defects, Protein Isoforms, Protein Structure, Tertiary, Sequence Alignment, Zebrafish
Show Abstract · Added February 19, 2015
p120-catenin (p120) modulates adherens junction (AJ) dynamics by controlling the stability of classical cadherins. Among all p120 isoforms, p120-3A and p120-1A are the most prevalent. Both stabilize cadherins, but p120-3A is preferred in epithelia, whereas p120-1A takes precedence in neurons, fibroblasts, and macrophages. During epithelial-to-mesenchymal transition, E- to N-cadherin switching coincides with p120-3A to -1A alternative splicing. These isoforms differ by a 101-amino acid "head domain" comprising the p120-1A N-terminus. Although its exact role is unknown, the head domain likely mediates developmental and cancer-associated events linked to p120-1A expression (e.g., motility, invasion, metastasis). Here we identified delta-interacting protein A (DIPA) as the first head domain-specific binding partner and candidate mediator of isoform 1A activity. DIPA colocalizes with AJs in a p120-1A- but not 3A-dependent manner. Moreover, all DIPA family members (Ccdc85a, Ccdc85b/DIPA, and Ccdc85c) interact reciprocally with p120 family members (p120, δ-catenin, p0071, and ARVCF), suggesting significant functional overlap. During zebrafish neural tube development, both knockdown and overexpression of DIPA phenocopy N-cadherin mutations, an effect bearing functional ties to a reported mouse hydrocephalus phenotype associated with Ccdc85c. These studies identify a novel, highly conserved interaction between two protein families that may participate either individually or collectively in N-cadherin-mediated development.
© 2014 Markham et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
1 Communities
2 Members
0 Resources
19 MeSH Terms
Slug regulates E-cadherin repression via p19Arf in prostate tumorigenesis.
Xie Y, Liu S, Lu W, Yang Q, Williams KD, Binhazim AA, Carver BS, Matusik RJ, Chen Z
(2014) Mol Oncol 8: 1355-64
MeSH Terms: Animals, Cadherins, Cyclin-Dependent Kinase Inhibitor p16, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, Humans, Male, Mice, Prostate, Prostatic Neoplasms, SUMO-1 Protein, Snail Family Transcription Factors, Transcription Factors
Show Abstract · Added January 20, 2015
SLUG represses E-cadherin to promote epithelial-mesenchymal transition (EMT) in various cancers. Mechanisms that regulate SLUG/E-cadherin pathway remain poorly understood, especially during tumorigenesis in vivo. Here we report that p19(Arf) (p14(ARF) in human) stabilizes Slug to inhibit E-cadherin in prostate cancer mouse models. Inactivation of p19(Arf) reduces Slug levels, resulting in increased E-cadherin expression and delaying the onset and progression of prostate cancer in Pten/Trp53 double null mice. Mechanistically, p14(ARF) stabilizes SLUG through increased sumoylation at lysine residue 192. Importantly, levels of SLUG and p14(ARF) are positively correlated in human prostate cancer specimens. These data demonstrated that ARF modulates the SLUG/E-cadherin signaling axis for augmenting prostate tumorigenesis in vivo, revealing a novel paradigm where the oncogenic functions of SLUG require ARF to target E-cadherin in prostate cancer. Collectively, our findings further support that ARF has dual tumor suppressive/oncogenic roles in cancers in a context-dependent manner.
Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
1 Communities
1 Members
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14 MeSH Terms
Intestinal brush border assembly driven by protocadherin-based intermicrovillar adhesion.
Crawley SW, Shifrin DA, Grega-Larson NE, McConnell RE, Benesh AE, Mao S, Zheng Y, Zheng QY, Nam KT, Millis BA, Kachar B, Tyska MJ
(2014) Cell 157: 433-446
MeSH Terms: Animals, COS Cells, Caco-2 Cells, Cadherins, Calcium, Carrier Proteins, Cell Cycle Proteins, Chlorocebus aethiops, Cytoskeletal Proteins, Disease Models, Animal, Enterocytes, HEK293 Cells, Humans, Mice, Mice, Knockout, Microvilli, Myosins, Usher Syndromes
Show Abstract · Added May 19, 2014
Transporting epithelial cells build apical microvilli to increase membrane surface area and enhance absorptive capacity. The intestinal brush border provides an elaborate example with tightly packed microvilli that function in nutrient absorption and host defense. Although the brush border is essential for physiological homeostasis, its assembly is poorly understood. We found that brush border assembly is driven by the formation of Ca(2+)-dependent adhesion links between adjacent microvilli. Intermicrovillar links are composed of protocadherin-24 and mucin-like protocadherin, which target to microvillar tips and interact to form a trans-heterophilic complex. The cytoplasmic domains of microvillar protocadherins interact with the scaffolding protein, harmonin, and myosin-7b, which promote localization to microvillar tips. Finally, a mouse model of Usher syndrome lacking harmonin exhibits microvillar protocadherin mislocalization and severe defects in brush border morphology. These data reveal an adhesion-based mechanism for brush border assembly and illuminate the basis of intestinal pathology in patients with Usher syndrome. PAPERFLICK:
Copyright © 2014 Elsevier Inc. All rights reserved.
1 Communities
1 Members
0 Resources
18 MeSH Terms
Excess PLAC8 promotes an unconventional ERK2-dependent EMT in colon cancer.
Li C, Ma H, Wang Y, Cao Z, Graves-Deal R, Powell AE, Starchenko A, Ayers GD, Washington MK, Kamath V, Desai K, Gerdes MJ, Solnica-Krezel L, Coffey RJ
(2014) J Clin Invest 124: 2172-87
MeSH Terms: Animals, Antigens, CD, Cadherins, Cell Line, Tumor, Colonic Neoplasms, Dual Specificity Phosphatase 6, Epithelial-Mesenchymal Transition, HEK293 Cells, Humans, Intestinal Mucosa, Mice, Mitogen-Activated Protein Kinase 1, Neoplasm Invasiveness, Neoplasm Proteins, Proteins, Vimentin, Zebrafish, Zebrafish Proteins
Show Abstract · Added May 27, 2014
The epithelial-to-mesenchymal transition (EMT) transcriptional program is characterized by repression of E-cadherin (CDH1) and induction of N-cadherin (CDH2), and mesenchymal genes like vimentin (VIM). Placenta-specific 8 (PLAC8) has been implicated in colon cancer; however, how PLAC8 contributes to disease is unknown, and endogenous PLAC8 protein has not been studied. We analyzed zebrafish and human tissues and found that endogenous PLAC8 localizes to the apical domain of differentiated intestinal epithelium. Colon cancer cells with elevated PLAC8 levels exhibited EMT features, including increased expression of VIM and zinc finger E-box binding homeobox 1 (ZEB1), aberrant cell motility, and increased invasiveness. In contrast to classical EMT, PLAC8 overexpression reduced cell surface CDH1 and upregulated P-cadherin (CDH3) without affecting CDH2 expression. PLAC8-induced EMT was linked to increased phosphorylated ERK2 (p-ERK2), and ERK2 knockdown restored cell surface CDH1 and suppressed CDH3, VIM, and ZEB1 upregulation. In vitro, PLAC8 directly bound and inactivated the ERK2 phosphatase DUSP6, thereby increasing p-ERK2. In a murine xenograft model, knockdown of endogenous PLAC8 in colon cancer cells resulted in smaller tumors, reduced local invasion, and decreased p-ERK2. Using MultiOmyx, a multiplex immunofluorescence-based methodology, we observed coexpression of cytosolic PLAC8, CDH3, and VIM at the leading edge of a human colorectal tumor, supporting a role for PLAC8 in cancer invasion in vivo.
0 Communities
3 Members
1 Resources
18 MeSH Terms
The integrin β1 subunit regulates paracellular permeability of kidney proximal tubule cells.
Elias BC, Mathew S, Srichai MB, Palamuttam R, Bulus N, Mernaugh G, Singh AB, Sanders CR, Harris RC, Pozzi A, Zent R
(2014) J Biol Chem 289: 8532-44
MeSH Terms: Animals, Cadherins, Cell Membrane Permeability, Cells, Cultured, Claudin-2, Down-Regulation, Epithelial Cells, Gene Deletion, Integrin beta1, Kidney Tubules, Proximal, Mice, Permeability, Up-Regulation, Urine
Show Abstract · Added February 25, 2014
Epithelial cells lining the gastrointestinal tract and kidney have different abilities to facilitate paracellular and transcellular transport of water and solutes. In the kidney, the proximal tubule allows both transcellular and paracellular transport, while the collecting duct primarily facilitates transcellular transport. The claudins and E-cadherin are major structural and functional components regulating paracellular transport. In this study we present the novel finding that the transmembrane matrix receptors, integrins, play a role in regulating paracellular transport of renal proximal tubule cells. Deleting the integrin β1 subunit in these cells converts them from a "loose" epithelium, characterized by low expression of E-cadherin and claudin-7 and high expression of claudin-2, to a "tight" epithelium with increased E-cadherin and claudin-7 expression and decreased claudin-2 expression. This effect is mediated by the integrin β1 cytoplasmic tail and does not entail β1 heterodimerization with an α-subunit or its localization to the cell surface. In addition, we demonstrate that deleting the β1 subunit in the proximal tubule of the kidney results in a major urine-concentrating defect. Thus, the integrin β1 tail plays a key role in regulating the composition and function of tight and adherens junctions that define paracellular transport properties of terminally differentiated renal proximal tubule epithelial cells.
1 Communities
5 Members
1 Resources
14 MeSH Terms