| Rho family GTPases are key regulators of diverse processes such as cytoskeletal organization, cell growth and differentiation, transcriptional regulation, and cell adhesion/motility. The activities of these proteins are controlled primarily through guanine nucleotide exchange factors (GEFs) that facilitate the exchange of GDP for GTP, promoting the active (GTP-bound) state, and GTPase activating proteins (GAPs) that promote GTP hydrolysis and the inactive (GDP-bound) state. The p190 RhoGAP proteins are widely expressed Rho family GAPs. p190-A has been characterized as a tumor suppressor, and research studies have shown that loss or rearrangement of the chromosomal region containing the gene for p190-A is linked to tumor development. p190-A binds the mitogen-inducible transcription factor TFII-I, sequestering it in the cytoplasm and inhibiting its activity. Phosphorylation of p190-A at Tyr308 reduces its affinity for TFII-I, relieving the inhibition. p190-A can also inhibit growth factor-induced gliomas in mice and affect cleavage furrow formation and cytokinesis in cultured cells. Mice lacking p190-B RhoGAP show excessive Rho activation and a reduction in activation of the transcription factor CREB. Cells deficient in p190-B display defective adipogenesis. There is increasing evidence that p190 undergoes tyrosine phosphorylation, which activates its GAP domain. Levels of tyrosine phosphorylation are enhanced by Src overexpression. IGF-I treatment downregulates Rho through phosphorylation and activation of p190-B RhoGAP, thereby enhancing IGF signaling implicated in adipogenesis. |
