A core function for p120-catenin in cadherin turnover

p120-catenin stabilizes epithelial cadherin (E-cadherin) in SW48 cells, but the mechanism has not been established. Here, we show that p120 acts at the cell surface to control cadherin turnover, thereby regulating cadherin levels. p120 knockdown by siRNA expression resulted in dose-dependent elimination of epithelial, placental, neuronal, and vascular endothelial cadherins, and complete loss of cell–cell adhesion. ARVCF and δ-catenin were functionally redundant, suggesting that proper cadherin-dependent adhesion requires the presence of at least one p120 family member. The data reveal a core function of p120 in cadherin complexes, and strongly predict a dose-dependent loss of E-cadherin in tumors that partially or completely down-regulate p120.

[1]  A. Bershadsky,et al.  p120 catenin affects cell motility via modulation of activity of Rho-family GTPases: a link between cell-cell contact formation and regulation of cell locomotion. , 2001, Journal of cell science.

[2]  K. Burridge,et al.  P120 Catenin Regulates the Actin Cytoskeleton via Rho Family Gtpases , 2000, The Journal of cell biology.

[3]  S. Parkhurst,et al.  Rho1 interacts with p120ctn and alpha-catenin, and regulates cadherin-based adherens junction components in Drosophila. , 2002, Development.

[4]  A. Reynolds,et al.  Altered expression of the catenin p120 in human cancer: implications for tumor progression. , 2002, Differentiation; research in biological diversity.

[5]  C. Niessen.  Faculty Opinions recommendation of A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. , 2002 .

[6]  A. Yap,et al.  The morphogenetic role of cadherin cell adhesion molecules in human cancer: a thematic review. , 1998, Cancer investigation.

[7]  Yi Zheng,et al.  Inhibition of RhoA by p120 catenin , 2000, Nature Cell Biology.

[8]  Keith R. Johnson,et al.  N-cadherin-Catenin Complexes Form Prior to Cleavage of the Proregion and Transport to the Plasma Membrane* , 2003, The Journal of Biological Chemistry.

[9]  M. Takeichi.  Morphogenetic roles of classic cadherins. , 1995, Current opinion in cell biology.

[10]  Gerhard Christofori,et al.  A causal role for E-cadherin in the transition from adenoma to carcinoma , 1998, Nature.

[11]  C. T. Anderson,et al.  Drosophila p120catenin plays a supporting role in cell adhesion but is not an essential adherens junction component , 2003, The Journal of cell biology.

[12]  W. Fiers,et al.  Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role , 1991, Cell.

[13]  L. Baki,et al.  Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[14]  R. Makino,et al.  Frequent down-regulation of E-cadherin by genetic and epigenetic changes in the malignant progression of hepatocellular carcinomas. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[15]  A. Kikuchi.  Regulation of beta-catenin signaling in the Wnt pathway. , 2000, Biochemical and biophysical research communications.

[16]  G. Berx,et al.  The role of the E-cadherin/catenin adhesion complex in the development and progression of cancer. , 1999, Molecular cell biology research communications : MCBRC.

[17]  R. Bernards,et al.  A System for Stable Expression of Short Interfering RNAs in Mammalian Cells , 2002, Science.

[18]  J. Daniel,et al.  Identification of a new catenin: the tyrosine kinase substrate p120cas associates with E-cadherin complexes , 1994, Molecular and cellular biology.

[19]  J. Parsons,et al.  Transformation-specific tyrosine phosphorylation of a novel cellular protein in chicken cells expressing oncogenic variants of the avian cellular src gene , 1989, Molecular and cellular biology.

[20]  W. Birchmeier,et al.  Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex , 2002, Nature Cell Biology.

[21]  G. Berx,et al.  The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. , 2001, Molecular cell.

[22]  F. Watt,et al.  Expression of a dominant negative cadherin mutant inhibits proliferation and stimulates terminal differentiation of human epidermal keratinocytes. , 1996, Journal of cell science.

[23]  Heinz Höfler,et al.  Mutations of the human E‐cadherin (CDH1) gene , 1998, Human mutation.

[24]  C. Kintner.  Regulation of embryonic cell adhesion by the cadherin cytoplasmic domain , 1992, Cell.

[25]  F. van Roy,et al.  A novel role for p120 catenin in E-cadherin function , 2002, The Journal of cell biology.

[26]  J. Bonifacino.  Protein Trafficking , 2005, Current protocols in cell biology.

[27]  W. Birchmeier,et al.  E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells , 1991, The Journal of cell biology.

[28]  M. Takeichi,et al.  Disruption of epithelial cell-cell adhesion by exogenous expression of a mutated nonfunctional N-cadherin. , 1993, Molecular biology of the cell.

[29]  Albert B. Reynolds,et al.  Selective Uncoupling of P120ctn from E-Cadherin Disrupts Strong Adhesion , 2000, The Journal of cell biology.

[30]  M. Vijver,et al.  E‐cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. , 1995, The EMBO journal.

[31]  W. Birchmeier,et al.  Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. , 1994, Biochimica et biophysica acta.

[32]  A. Reynolds,et al.  Regulation of Rho GTPases by p120-catenin. , 2001, Current opinion in cell biology.

[33]  J. Stow,et al.  Recycling of E-cadherin: a potential mechanism for regulating cadherin dynamics. , 1999 .

[34]  L. Hicke.  Gettin' down with ubiquitin: turning off cell-surface receptors, transporters and channels. , 1999, Trends in cell biology.

[35]  P. Polakis.  Wnt signaling and cancer. , 2000, Genes & development.

[36]  P. Rørth,et al.  Binding site for p120/δ-catenin is not required for Drosophila E-cadherin function in vivo , 2003, The Journal of cell biology.

[37]  A. Reynolds,et al.  The p120 catenin family: complex roles in adhesion, signaling and cancer. , 2000, Journal of cell science.

[38]  K. Miyazawa,et al.  Association of p120, a tyrosine kinase substrate, with E- cadherin/catenin complexes , 1995, The Journal of cell biology.

[39]  J. Cleveland,et al.  p120, a novel substrate of protein tyrosine kinase receptors and of p60v-src, is related to cadherin-binding factors beta-catenin, plakoglobin and armadillo. , 1992, Oncogene.

[40]  A. Reynolds,et al.  Identification of Src Phosphorylation Sites in the Catenin p120 ctn * , 2001, The Journal of Biological Chemistry.

[41]  G. Serban,et al.  A presenilin‐1/γ‐secretase cleavage releases the E‐cadherin intracellular domain and regulates disassembly of adherens junctions , 2002, The EMBO journal.

[42]  K. Kosik,et al.  δ-catenin, an Adhesive Junction–associated Protein Which Promotes Cell Scattering , 1999, The Journal of cell biology.

[43]  J. Stow,et al.  Protein kinase C regulates endocytosis and recycling of E-cadherin. , 2002, American journal of physiology. Cell physiology.

[44]  S. Hirohashi,et al.  E-cadherin gene mutations in human gastric carcinoma cell lines. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[45]  J. Hardin,et al.  The Caenorhabditis elegans p120 catenin homologue, JAC-1, modulates cadherin–catenin function during epidermal morphogenesis , 2003, The Journal of cell biology.

[46]  A. Starzinski-Powitz,et al.  mARVCF cellular localisation and binding to cadherins is influenced by the cellular context but not by alternative splicing. , 2001, Journal of cell science.

[47]  A. Kikuchi.  Regulation of β-Catenin Signaling in the Wnt Pathway , 2000 .

[48]  M. Takeichi,et al.  The 102 kd cadherin-associated protein: Similarity to vinculin and posttranscriptional regulation of expression , 1991, Cell.

[49]  V. Faundez,et al.  Mechanisms of VE-cadherin Processing and Degradation in Microvascular Endothelial Cells* , 2003, Journal of Biological Chemistry.