Abstract

Dynamic modulation of cell adhesion is integral to a wide range of biological processes. The small guanosine triphosphatase Rap1 is an important regulator of cell - cell and cell - matrix adhesions. We show here that induced expression of activated Abl tyrosine kinase reduces Rap1-GTP levels through phosphorylation of Tyr221 of CrkII, which disrupts interaction of CrkII with C3G, a guanine nucleotide exchange factor for Rap1. Abl-dependent down-regulation of Rap1-GTP causes cell rounding and detachment only when the Rho - ROCK1 pathway is also activated, for example, by lysophosphatidic acid. During ephrin-A1 - induced retraction of PC3 prostate cancer cells, we show that endogenous Abl is activated and disrupts the CrkII - C3G complex to reduce Rap1-GTP. Interestingly, ephrin-A1 - induced PC3 cell retraction also requires LPA, which stimulates Rho to a much higher level than that is activated by ephrin-A1. Our results establish Rap1 as another downstream target of the Abl - CrkII signaling module and show that Abl - CrkII collaborates with Rho - ROCK1 to stimulate cell retraction. © 2008 Huang et al.