RAS-family GTPase (RAS GTPase)

RAS-family GTPases are a subfamily of 35-36 small guanosine triphosphate (GTP) hydrolases (GTPases) within the larger RAS superfamily, acting as molecular binary switches that cycle between inactive GDP-bound and active GTP-bound conformations to regulate key cellular processes. In the GTP-bound state, they engage effector proteins via conserved switch regions, activating downstream pathways like RAF-MEK-ERK for proliferation, PI3K-AKT for survival, and RALGDS-RAL for trafficking and migration. Classical members HRAS, KRAS, and NRAS are frequently mutated in cancers, locking them in the active state by impairing GTP hydrolysis and GAP responsiveness, thereby driving oncogenesis through hyperactive signaling. Other subfamily members, such as those in distal-RAS (DIRAS, RASD, RASL10) and CaaX-less RAS groups, often exhibit tumor-suppressive roles and are downregulated in tumors. Regulation involves guanine nucleotide exchange factors (GEFs) for GTP loading and GTPase-activating proteins (GAPs) for hydrolysis, ensuring tight control. Therapeutic targeting is challenging due to the proteins' high GTP affinity and picomolar effector binding, but emerging inhibitors disrupt effector interactions or stabilize inactive states. These GTPases localize to membranes via lipid modifications, influencing diverse functions from mitogenesis to apoptosis.

Other names

RAS proteinsRAS superfamily small GTPasesclassical RAS (HRAS, KRAS, NRAS)

Inhibition of GTP-bound active conformation, stabilization of RAS-GAP interactions to enhance GTP hydrolysis, steric hindrance of RAS-effector binding