p120GAP

p120GAP, also known as p120 GTPase-activating protein, is a member of the Ras GTPase-activating protein (RasGAP) family. In humans it is encoded by the RASA1 gene. p120GAP functions as a negative regulator of Ras signaling by accelerating the hydrolysis of GTP bound to Ras, converting Ras-GTP to Ras-GDP and thereby downregulating the Ras-MAPK pathway. It also participates in signaling cross-talk and receptor trafficking events at the plasma membrane.

Structure and mechanism: p120GAP contains two N-terminal SH2 domains that recognize phosphotyrosine-containing motifs and a C-terminal catalytic GAP-related domain that stimulates Ras GTP hydrolysis. The SH2 domains facilitate recruitment to activated receptor tyrosine kinases and their associated signaling complexes, placing the catalytic domain in proximity to Ras. Through this arrangement, p120GAP modulates signal throughput in response to growth factor stimulation and receptor activation. Isoforms produced by alternative splicing can differ in regulatory regions while preserving the GAP activity.

Regulation and cellular roles: The activity and localization of p120GAP are influenced by phosphorylation, protein–protein interactions with adaptors such as Grb2 and Shc, and cellular context. By inactivating Ras at the membrane, p120GAP helps terminate proliferative signals and can participate in broad regulatory networks that influence cell growth, differentiation, and migration. Crosstalk with other small GTPase pathways, including Rho family signaling, has also been noted in some contexts.

Clinical significance: Mutations in RASA1, the gene encoding p120GAP, cause capillary malformation-arteriovenous malformation (CM-AVM) syndrome, characterized by congenital capillary malformations and arteriovenous malformations. Both germline and somatic variants have been linked to vascular anomalies, and animal models implicate p120GAP in angiogenesis and vascular development.

See also: Ras GTPase-activating proteins; RASA family; Ras-MAPK signaling.