RasGDP

RasGDP is the GDP-bound form of the Ras family of small GTPases, which function as molecular switches in many cellular signaling pathways. Ras proteins cycle between an inactive RasGDP state and an active RasGTP state to regulate processes such as cell growth, differentiation, and survival.

Regulation of the Ras switch is controlled by regulatory proteins. Guanine nucleotide exchange factors (GEFs) promote the release of GDP and binding of GTP, activating Ras. GTPase-activating proteins (GAPs) accelerate the intrinsic GTP hydrolysis activity, returning Ras to the RasGDP state and turning signaling off. In the absence of regulators, Ras retains slow intrinsic GTPase activity, gradually reverting to RasGDP.

Localization and structure play important roles in Ras function. Ras proteins are anchored to the inner leaflet of the plasma membrane through lipid modifications, and the nucleotide bound influences conformation and effector binding. The RasGDP form adopts an inactive conformation that is not competent to engage most downstream effectors.

Pathways and effectors: When Ras is bound to GTP, it interacts with downstream effectors such as RAF kinases, PI3K, and RalGDS, initiating signaling cascades including the MAPK and PI3K-AKT pathways. RasGDP does not effectively activate these pathways, reflecting its inactive state.

Clinical relevance: Oncogenic mutations in Ras often impair GTP hydrolysis or promote GDP-GTP exchange, biasing signaling toward constitutive RasGTP activity and contributing to uncontrolled cell proliferation. Therapeutic strategies frequently aim to disrupt the GDP-GTP cycle, membrane localization, or effector interactions to dampen Ras-driven signaling.

In research, the balance between RasGDP and RasGTP is used to gauge Ras pathway activity. Assays and biosensors that distinguish nucleotide state help characterize signaling dynamics in cells.