P190 RhoGAP functions in tissue morphogenesis

Abstract

The p190 family of Rho GTPase activating proteins (GAPs) includes two closely related proteins, p190A and p190B, that are potent inhibitors of Rho GTPase activity. They can each be regulated in response to the engagement of cell surface adhesion molecules, such as integrins, as well as by activated growth factor receptors, and they play essential roles in mouse embryogenesis. However, they appear to mediate distinct signaling pathways by virtue of non-overlapping sites of regulatory phosphorylation. For p190A, src kinases are important regulators of activity and p190A is the principal substrate of src kinase-mediated phosphorylation in the brain. In addition, growth factor receptors, such as the PDGF receptor, can directly phosphorylate p190A on one of its so-called FF domains. As a consequence, p190A dissociates from the transcription factor, TFII-I, which becomes free to translocate to the nucleus to activate gene transcription. p190B is regulated through distinct mechanisms. p190B can be directly phosphorylated on a single identified tyrosine residue by the activated insulin and IGF-1 receptors. This phosphorylation causes p190B to translocate to the lipid rafts of the plasma membrane, where it can potentially facilitate the inactivation of the Rho GTPase, which also becomes enriched within the lipid rafts. Thus, upon insulin/IGF-1 signaling, phosphorylation of p190B can promote Rho inactivation. Mechanisms by which p190B may function to link IGF-1 and integrin-mediated signals that influence Rho-dependent actin reorganization will be presented.