p190RhoGAPs

p190RhoGAPs are a family of Rho GTPase-activating proteins that regulate signaling through Rho family GTPases by accelerating their intrinsic GTPase activity, thereby inactivating the pathway. In humans, the best characterized members are p190A RhoGAP (ARHGAP35) and p190B RhoGAP (ARHGAP5). They were originally identified as substrates of the Src family tyrosine kinase pp60src, linking Rho signaling to Src-driven pathways that control the actin cytoskeleton and cell behavior. The proteins contain regulatory regions in addition to a central RhoGAP catalytic domain that modulates their activity and interactions.

The catalytic GAP domain enables p190RhoGAPs to promote GTP hydrolysis on Rho family GTPases, with activity toward RhoA, RhoB, and RhoC among others. Their subcellular localization is dynamic, including cytosolic, membrane-associated, and endosomal compartments, and their activity is tuned by phosphorylation and interactions with signaling adaptors. Phosphorylation by Src family kinases and binding to SH2-domain-containing proteins help control their localization and function.

Biologically, p190RhoGAPs influence actin cytoskeleton remodeling, cell adhesion, and migration by antagonizing RhoA signaling. They play roles in development and physiology, including neuronal migration and axon guidance, as well as hematopoietic cell behavior. Dysregulation of p190RhoGAPs has been linked to cancer progression and metastasis in a context-dependent manner, with evidence for both tumor-suppressive and pro-migratory roles depending on tissue and signals. As central regulators of Rho signaling, p190RhoGAPs continue to be studied to understand cytoskeletal control and its implications for development and disease.