P-catenin is a component of the cadherin adhesion protein complex and an intracellular signal transducing protein in the Wnt pathway, p-catenin is regulated by the ARC tumor suppressor protein, and mutations in both p-catenin and E-cadherin are implicated in many forms of cancer. The two overall objectives of the project are to determine the mechanism underlying the cytoplasmic regulation of p-catenin signaling, and to determine how cadherins affect p-catenin signaling, cell differentiation, and tumor cell growth. Nuclear import of p-catenin is important for signaling and occurs by a novel mechanism involving its interaction with the nuclear pore. The mechanism of p-catenin nuclear pore docking and its regulation by the Wnt signaling pathway will be studied, p-catenin signaling is regulated by a very large protein complex that includes ARC, axin, and the kinase GSKSp. The properties of the intact complex will be studied using an in vitro p-catenin signaling assay, phosphorylation assays, and analyses of p-catenin interactions. The complex will also be purified in order to identify key protein components. Furthermore, the role of a recently identified second ARC protein, APC-2, in p-catenin signaling in the early Xenopus embryo will be evaluated. Cadherin expression antagonizes p-catenin signaling by binding it up at the plasma membrane, providing a potential mechanism to couple changes in cell adhesion to regulation of gene expression. The possibility that cadherin regulation of p-catenin signaling plays an important role in development of the neural crest in the Xenopus embryo, an epithelial-mesenchymal transition, will be explored. Similarly, experiments will be done to determine the relative contributions of regulating P-cateninsignaling or enhancing cell adhesion to the tumor suppressor function of E-cadherin. Experiments will also be performed to determine whether E-cadherin can directly generate signals that mediate contact inhibition of cell growth. These experiments should help us understand the mechanisms of p-catenin-mediated signaling and provide insights into the relationships between cell adhesion, tissue morphogenesis, and tumor growth.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM037432-22
Application #
7163488
Study Section
Special Emphasis Panel (NSS)
Program Officer
Deatherage, James F
Project Start
1987-01-01
Project End
2009-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
22
Fiscal Year
2007
Total Cost
$524,262
Indirect Cost
Name
University of Virginia
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Park, Ki-Sook; Gumbiner, Barry M (2012) Cadherin-6B stimulates an epithelial mesenchymal transition and the delamination of cells from the neural ectoderm via LIMK/cofilin mediated non-canonical BMP receptor signaling. Dev Biol 366:232-43
Kim, Nam Hee; Kim, Hyun Sil; Kim, Nam-Gyun et al. (2011) p53 and microRNA-34 are suppressors of canonical Wnt signaling. Sci Signal 4:ra71
Kim, Nam-Gyun; Koh, Eunjin; Chen, Xiao et al. (2011) E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components. Proc Natl Acad Sci U S A 108:11930-5
Park, Ki-Sook; Gumbiner, Barry M (2010) Cadherin 6B induces BMP signaling and de-epithelialization during the epithelial mesenchymal transition of the neural crest. Development 137:2691-701
Kim, Nam-Gyun; Xu, Chong; Gumbiner, Barry M (2009) Identification of targets of the Wnt pathway destruction complex in addition to beta-catenin. Proc Natl Acad Sci U S A 106:5165-70
Xu, Chong; Kim, Nam-Gyun; Gumbiner, Barry M (2009) Regulation of protein stability by GSK3 mediated phosphorylation. Cell Cycle 8:4032-9
Vonica, Alin; Gumbiner, Barry M (2007) The Xenopus Nieuwkoop center and Spemann-Mangold organizer share molecular components and a requirement for maternal Wnt activity. Dev Biol 312:90-102
Mahadevaiyer, Sreekala; Xu, Chong; Gumbiner, Barry M (2007) Characterization of a 60S complex of the adenomatous polyposis coli tumor suppressor protein. Biochim Biophys Acta 1773:120-30
Perrais, Michael; Chen, Xiao; Perez-Moreno, Mirna et al. (2007) E-cadherin homophilic ligation inhibits cell growth and epidermal growth factor receptor signaling independently of other cell interactions. Mol Biol Cell 18:2013-25
Chen, Xuejun; Gumbiner, Barry M (2006) Crosstalk between different adhesion molecules. Curr Opin Cell Biol 18:572-8

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