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Functional Characterization of p115 RhoGEF

2002; Academic Press; Linguagem: Inglês

10.1016/s0076-6879(02)45030-6

1557-7988

Clark D. Wells, Xuejun Jiang, Stephen Gutowski, Paul C. Sternweis,

PI3K/AKT/mTOR signaling in cancer

The Rho family of monomeric GTPases plays a prominent role in the regulation of cell shape and movement. The activity of these proteins is dependent on a nucleotide cycle that is regulated by a combination of guanine nucleotide exchange factors (GEFs) that facilitate exchange of GTP for GDP on the Rho proteins, and GTPase-activating proteins (GAPs) that stimulate hydrolysis of GTP bound to Rho. The GEFs promote activation, that is, formation of the GTP-bound state, whereas proteins with GAP function serve to inactivate the GTPases. The heterotrimeric G proteins that mediate regulation by a variety of extracellular stimuli are also controlled by a GDP/GTP cycle. Integral membrane receptors for detection of hormones and other stimuli act as the GEFs to provide stimulatory inputs and a family of RGS (regulator of G protein signaling) proteins as GAPs that can effect either inhibitory or downstream regulation. The GEFs for the Rho family of GTPases compose a large and growing family of proteins characterized by conserved, tandem DH (Dbl homology) and PH (pleckstrin homology) domains. These exchange factors stimulate Rho proteins with various selectivities for three defined functional groups represented by RhoA, Racl, and Cdc42. p115 RhoGEF has been purified and cloned as a GEF that is selective for Rho. The subsequent identification of an RGS domain in the N terminus of p115, which has specificity for the G12 family of heterotrimeric G proteins, and the regulation of GEF activity by the activated Ga∼3 subunit, defines this protein as a direct link for coupling regulation between these two G protein pathways.