RasGAPs

Ras GTPase-activating proteins (RasGAPs) are a diverse family of proteins that regulate signaling by the Ras family of small GTPases. They accelerate the intrinsic GTPase activity of Ras, promoting hydrolysis of GTP to GDP, thereby converting Ras from an active GTP-bound state to an inactive GDP-bound state and turning off Ras-driven signaling cascades such as the RAF-MEK-ERK pathway.

Most RasGAPs contain a catalytic Ras-GAP domain responsible for stimulating GTP hydrolysis. Many members also possess additional regulatory domains that mediate interactions with phosphotyrosine-containing proteins, lipids, or other signaling regulators (for example SH2, SH3, PH domains). Notable RasGAPs include NF1 (neurofibromin), RASA1 (p120GAP), RASA2, RASA3, and DAB2IP, as well as specialized proteins like SynGAP that function in neurons. These proteins often act at the plasma membrane or endomembrane compartments, and their activity can be controlled by phosphorylation, protein-protein interactions, and subcellular localization.

RasGAPs serve as negative regulators of Ras signaling and influence cellular processes such as proliferation, differentiation, migration, and survival. Their activity integrates with receptor tyrosine kinase signaling, Ras guanine nucleotide exchange factors (GEFs), and other regulators to shape the amplitude and duration of Ras pathway activation. Loss-of-function mutations or decreased expression of RasGAPs can lead to sustained Ras activity and contribute to cancer or developmental disorders; conversely, some RasGAPs can function as tumor suppressors.

Despite sharing a common catalytic mechanism, RasGAPs display considerable diversity in substrate specificity and cellular roles, and ongoing research continues to define their context-dependent functions across tissues and diseases.