Reactome | RAS GAPs bind RAS:GTP

RAS GAPs bind RAS:GTP

Stable Identifier

R-HSA-5658435

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane

ReviewStatus

5/5

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The human genome encodes at least 10 proteins that bind RAS and activate its intrinsic GTPase activity, resulting in the formation of inactive RAS:GDP and attenuating RAS signaling (reviewed in King et al, 2013). These identified RAS GAP proteins are RASA1 (also known as p120 GAP), NF1, the GAP1 family (RASA2, RASA3, RASA4 and RASAL1) and the SYNGAP family (SYNGAP1, DAB2IP, RASAL2 and RASAL3). GAP proteins stimulate RAS GTPase activity by inserting a conserved arginine residue into the RAS active site, promoting a conformational change in the active site to allow GTP hydrolysis (Ahamdian et al, 2003; Scheffzek et al, 1997; Ahamdian et al, 1997). In addition to the GAP domain, most RAS GAP proteins also contain membrane targeting domains that facilitate interaction with the plasma membrane where RAS is tethered. In some cases, such as RASA3, membrane localization is constitutive, whereas in others, the GAP proteins are targeted to the membrane in response to cellular signaling. In addition to binding RAS, a number of GAP proteins also mediate other protein-protein interactions and act as scaffolds to integrate signaling; some GAPs are also known to bind and activate other small GTPases such as RAP (reviewed in King et al, 2013). Loss-of-functions mutations in RAS GAP proteins have been identified in a number of cancers (reviewed in Maertens and Cichowski, 2014).

Literature References

PubMed ID	Title	Journal	Year
23443682	Nonredundant functions for Ras GTPase-activating proteins in tissue homeostasis Lapinski, PE, Lubeck, BA, King, PD	Sci Signal	2013
12787671	Structural fingerprints of the Ras-GTPase activating proteins neurofibromin and p120GAP Scheffzek, K, Ahmadian, MR, Stege, P, Kiel, C	J. Mol. Biol.	2003
9302992	Confirmation of the arginine-finger hypothesis for the GAP-stimulated GTP-hydrolysis reaction of Ras Scheffzek, K, Ahmadian, MR, Wittinghofer, A, Stege, P	Nat. Struct. Biol.	1997
9219684	The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants Lautwein, A, Ahmadian, MR, Schmitz, F, Kabsch, W, Wittinghofer, A, Wiesmuller, L, Scheffzek, K	Science	1997