): Much attention has been focused recently on E-(epithelial)-cadherin and its role in cell-cell adhesion and tumor invasiveness. In approximately 50 percent of metastatic carcinomas, E-cadherin expression is downregulated or lost altogether, and this is thought to figure prominently in tumor metastasis. Research in the applicant's laboratory has identified a novel catenin, p120ctn, and demonstrated that its association with E-cadherin is required for tight cell-cell adhesion. Conflicting data suggest that pl20 can act both positively and negatively on junction assembly depending on signaling cues that remain unspecified. A working model is presented suggesting that p120 acts as a switch that regulates cadherin clustering, a key event in the formation of nascent cell-cell junctions.
Aim 1 seeks to identify the role of p120 tyrosine and serine phosphorylation in this process through mapping of the relevant phosphorylation sites and strategies aimed at specific inhibition of their roles. In addition, preliminary data indicate a novel RhoA-specific GDI-like function for p120, potentially explaining the dependence of cadherin clustering on both p120 and RhoA activities. p120 mutants have been generated that bind cadherins normally but are functionally uncoupled from RhoA.
Aim 2 seeks to clarify this functional relationship through (1) characterizing the p120 - RhoA binding interaction in vitro, and (2) functional experiments designed around the RhoA - uncoupled p120 mutants. The crucial relationship between E-cadherin, p120, and RhoA is probably disrupted in metastatic cells, where cadherins are frequently absent or dysfunctional, and in cells expressing various oncogenes such as Src and Ras, which require RhoA activity for their transforming functions. Although Aims 1 and 2 are designed as independent modules, several lines of evidence suggest that phosphorylation of p120 impacts directly on its ability to regulate RhoA function in cell-cell contacts Together, the complimentary experiments outlined in these aims should significantly clarify the role of pl20 in cadherin function.
Showing the most recent 10 out of 22 publications
