RasGTPasen

Ras GTPases, also known in German as RasGTPasen, are a family of small GTP-binding proteins that act as central regulators of intracellular signaling. They belong to the Ras superfamily and function as molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state.

Activation begins when guanine nucleotide exchange factors (GEFs), such as SOS proteins, promote the release of GDP so that GTP can bind. GTP hydrolysis, which returns Ras to its inactive form, is accelerated by GTPase-activating proteins (GAPs). Ras proteins are associated with membranes through post-translational lipid modifications and, for some isoforms, additional targeting motifs, ensuring they can interact with membrane-anchored effectors.

When in the GTP-bound state, Ras engages a set of downstream effector proteins, including RAF kinases, phosphoinositide 3-kinase (PI3K), and Ral guanine nucleotide dissociation stimuli (RalGDS). These interactions activate major signaling cascades such as the RAF–MEK–ERK MAP kinase pathway and the PI3K–AKT–mTOR pathway, coordinating processes like cell growth, differentiation, survival, and metabolism.

Biological and clinical relevance is substantial. Mutations in RAS genes—particularly KRAS, NRAS, and HRAS—are among the most common oncogenic events in human cancers, often affecting residues G12, G13, or Q61 and stabilizing the GTP-bound active form. Germline mutations in RAS genes contribute to RASopathies, a family of developmental disorders.

Therapeutically, targeting Ras has been challenging, but progress includes covalent inhibitors for mutant KRAS G12C and approaches aimed at blocking farnesylation or effector interactions. Ras signaling remains a focus of cancer biology and targeted therapy research.