When a cell receives extracellular signals it may need to activate or turn on a number of downstream signaling pathways in order to initiate a particular cellular response. Complex and specific responses can be coordinated by G-proteins, or GTPases, which function as molecular on/off switches that link extracellular signals to a variety of downstream signaling modules. GTPases hydrolyze GTP and cycle between two conformational states depending on whether GTP (guanine triphosphate) or GDP (guanine diphosphate) is bound. The GTP-bound GTPase is active, while the GDP-bound is inactive. In its active GTP-bound state, GTPases recognize and interact with specific target effectors that propagate downstream signals. GTPase activity is regulated by activators called GEFs (guanine-nucleotide exchange factors) and inactivators called GAPs (GTPase-activating proteins). GEFs transduce signals from receptor tyrosine kinases, G-protein-coupled receptors, adhesion molecules, and second messengers and promote GTP binding to GTPases. GTP binding and signaling to target effectors is in turn terminated by the hydrolysis of GTP to GDP facilitated by GAPs. A third class of GTPase regulators, the GDIs (G-nucleotide dissociation inhibitors), also exists. GDIs are specific regulators of the Rho/Rac and Rab families of monomeric GTPases. GDIs influence G-protein signaling by binding the GDP or GTP form of the GTPase and preventing dissociation of the nucleotide. Hundreds of GTPase regulators have been identified and the G-protein signaling system is conserved well through evolution. The involvement of G-protein signaling in a wide variety of cellular activities has resulted in the study of GTPases and their regulators as therapeutic targets in a number of human diseases.
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