RAS GTPase mutants don't hydrolyze GTP

Stable Identifier
R-HSA-6802834
Type
Reaction [transition]
Species
Homo sapiens
Compartment
plasma membrane
ReviewStatus
5/5
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RAS GTPase mutants don't hydrolyze GTP
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RAS is mutated in 25-30% of human cancers, with the majority of tumors carrying mutations at G12, G13 or Q61. Mutation at these sites interferes with the intrinsic and GAP-mediated hydrolysis of GTP, allowing the GTP bound form to persist and promote constitutive signaling (reviewed in Prior et al, 2012; Pylayeva and Gupta, 2011, King et al, 2013; Cox and Der, 2010). RAS GAP proteins interact with RAS by inserting an arginine finger into the RAS active site to promote positioning of the catalytic Q61 residue, stimulating the low intrinsic GTPase activity by several orders of magnitude (Ahmadian et al, 2003; Ahmadian et al, 1997; reviewed in Bos et al, 2007). Mutation of the catalytic Q61 disrupts coordination of a water molecule that is required for nucleophilic attack on the gamma phosphate of GTP, while G12 and G13 mutations abrogate interactions with RAS GAP proteins that are required for proper positioning of the Q61 residue (Trahey et al, 1987; Scheidig et al, 1999; Buhrman et al, 2010; Scheffzek et al,1997).
In addition to somatic mutations in cancer, RAS is also subject to germline mutations that lead to a group of developmental disorders collectively known as RASopathies (reviewed in Rauen, 2013; Tidyman and Rauen, 2009). Like their oncogenic counterparts, these RAS mutants show defective GTP hydrolysis and constitutive signaling (Schubbert et al, 2006; Schubbert et al, 2007).
Literature References
PubMed ID Title Journal Year
19467855 The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation

Tidyman, WE, Rauen, KA

Curr. Opin. Genet. Dev. 2009
20194776 Allosteric modulation of Ras positions Q61 for a direct role in catalysis

Fetics, S, Holzapfel, G, Mattos, C, Buhrman, G

Proc. Natl. Acad. Sci. U.S.A. 2010
21993244 RAS oncogenes: weaving a tumorigenic web

Grabocka, E, Pylayeva-Gupta, Y, Bar-Sagi, D

Nat. Rev. Cancer 2011
17540168 GEFs and GAPs: critical elements in the control of small G proteins

Wittinghofer, A, Rehmann, H, Bos, JL

Cell 2007
10574788 The pre-hydrolysis state of p21(ras) in complex with GTP: new insights into the role of water molecules in the GTP hydrolysis reaction of ras-like proteins

Goody, RS, Scheidig, AJ, Burmester, C

Structure 1999
17875937 Biochemical and functional characterization of germ line KRAS mutations

Niemeyer, CM, Shannon, K, Nguyen, H, Zenker, M, Lyubynska, N, Schubbert, S, Kratz, CP, Molven, A, Bollag, G

Mol. Cell. Biol. 2007
12787671 Structural fingerprints of the Ras-GTPase activating proteins neurofibromin and p120GAP

Scheffzek, K, Ahmadian, MR, Stege, P, Kiel, C

J. Mol. Biol. 2003
22589270 A comprehensive survey of Ras mutations in cancer

Lewis, PD, Mattos, C, Prior, IA

Cancer Res. 2012
2821624 A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants

McCormick, F, Trahey, M

Science 1987
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
21686117 Ras history: The saga continues

Der, CJ, Cox, AD

Small GTPases 2010
23875798 The RASopathies

Rauen, KA

Annu Rev Genomics Hum Genet 2013
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
16474405 Germline KRAS mutations cause Noonan syndrome

Kalscheuer, V, Niemeyer, CM, Nguyen, H, Zenker, M, Zhang, KY, Wehner, LE, Klein, C, West, B, Shannon, K, Rauch, A, Schubbert, S, Kratz, CP, van der Burgt, I, Bollag, G, Rowe, SL, Sistermans, E, Musante, L, Böll, S

Nat. Genet. 2006
23443682 Nonredundant functions for Ras GTPase-activating proteins in tissue homeostasis

Lapinski, PE, Lubeck, BA, King, PD

Sci Signal 2013
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Normal reaction
RAS intrinsic GTPase activity hydrolyzes GTP to GDP (Homo sapiens)
Functional status

Loss of function of RAS GTPase mutants:GTP [plasma membrane]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Authored
Rothfels, K  (2015-05-18)
Reviewed
Gavathiotis, E  (2020-05-04)
Created
Rothfels, K  (2015-10-02)
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