Integration of receptor tyrosine kinase, integrin, and cadherin activities is crucial for normal cell growth, motility, and adhesion. Here, we describe roles for p120-catenin (p120) and p190RhoGAP that coordinate crosstalk between these systems and regulate cadherin function. Surprisingly, PDGFR-induced actin remodeling in NIH3T3 cells is blocked in the absence of p120, and the cells are partially transformed via constitutive activation of Rho. We have traced the mechanism to unexpected codependent roles for p120 and p190RhoGAP in regulating Rac-dependent antagonism of Rho. Receptor-induced Rac activity causes translocation of p190RhoGAP to adherens junctions (AJs), where it couples to the cadherin complex via interaction with p120. AJ formation is dependent on this p120-p190RhoGAP interaction and fails altogether if either of these proteins are compromised. We propose that Rac activation links diverse signaling systems to AJ assembly by controlling transient p190RhoGAP interactions with p120 and localized inhibition of Rho.

The p53 tumor suppressor protein plays a critical role in the regulation of the cell cycle and apoptosis. The importance of p53's functions is underscored by the high incidence of p53 mutations in human cancers. Recently, two p53-related proteins, p73 and p63, were identi®ed as members of the p53 gene family. Multiple isoforms of p73 have been found, including DN variants in which the N-termini are truncated. p63 is expressed as three major forms, p63a, p63b and p63g, each of which di er in their C-termini. All three forms can be alternatively transcribed from a cryptic promoter located within intron 3, producing DNp63a, DNp63b and DNp63g. The high degree of similarity of p73 and p63 to evolutionarily conserved regions of p53 suggests that these proteins play an important and potentially redundant role in regulating cell cycle arrest and apoptosis. Here we describe the characterization of cell lines generated to inducibly express p63a and DNp63a. We have found that p63a and DNp63a can di erentially regulate endogenous p53 target genes and induce cell cycle arrest and apoptosis. Deletion of the N-terminal 26 amino acids of DNp63a abolished its ability to transactivate p53 target genes and induce cell cycle arrest and apoptosis. This indicates that a putative transactivation domain exists within the N-terminus of the DN variants of p63. Furthermore, the di erential regulation of p53 target genes by p63a and DNp63a suggests that p63 and p53 utilize both similar and di erent signaling pathways to execute their cellular functions. Oncogene (2001) 20, 3193 ± 3205.

No abstract

p120-catenin regulates epithelial cadherin stability and has been suggested to function as a tumor suppressor. In this study, we used anchorage-independent growth (AIG), a classical in vitro tumorigenicity assay, to examine the role of p120 in a different context, namely oncogene-mediated tumorigenesis. Surprisingly, p120 ablation by short hairpin RNA completely blocked AIG induced by both Rac1 and Src. This role for p120 was traced to its activity in suppression of the RhoA–ROCK pathway, which appears to be essential for AIG. Remarkably, the AIG block associated with p120 ablation was completely reversed by inhibition of the downstream RhoA effector ROCK. Harvey-Ras (H-Ras)–induced AIG was also dependent on suppression of the ROCK cascade but was p120 independent because its action on the pathway occurred downstream of p120. The data suggest that p120 modulates oncogenic signaling pathways important for AIG. Although H-Ras bypasses p120, a unifying theme for all three oncogenes is the requirement to suppress ROCK, which may act as a gatekeeper for the transition to anchorage independence.

We show that Rho-associated protein kinase 1 coimmunoprecipitates with p120 and colocalizes to adherens junctions. p120 links ROCK1 to E-cadherin, as ROCK1 associates with wild-type, but not p120-uncoupled, E-cadherin. These data suggest that p120 regulates Rho activity at the cadherin complex via interaction with up- and downstream effectors, including ROCK1.