Small GTPases

Many cytoplasmic signaling pathways involve small GTPases. Small GTPases are 20-30 kDa enzymes that catalyze the hydrolysis of GTP to GDP and are a subset of G proteins. Two important subfamilies of small GTPases are the Ras family and the Rho family.

Ras GTPase Family

Downstream of receptor tyrosine kinases, GPCRs, and focal adhesions, Ras GTPases act as integrators of extracellular signals and transduce these signals into intracellular responses, resulting in survival, differentiation, and proliferation. Ras GTPases signal through multiple downstream pathways, including the MAP kinase/ERK pathway, the PI3 kinase /Akt pathway, and the RalGDS pathway. Mutations in Ras protooncogenes are found in 20-30% of cancers, making Ras signaling pathways attractive targets for therapy.

Cytoskeletal Signaling: Rho GTPases

Cytoskeletal signaling complexes include GTPase complexes, focal adhesions, and adherens junctions. The Rho family of small GTPases transmit mechanical signals from the plasma membrane. Rho family members Rac, Rho and Cdc42 regulate the assembly of actin-based lamellipodia, stress fibers and filopodia, respectively. They also mediate polarity, proliferation, apoptosis, membrane transport, and gene expression. Focal adhesions and adherens junctions are membrane-associated complexes that link the cell exterior to the plasma membrane and the actin cytoskeleton. Focal adhesions are key initiators of signaling in response to adhesion.