RAS p21 protein activator 1

RAS p21 protein activator (GTPase activating protein) 1

PDB rendering based on 1wer.

Available structures
PDB	1WER, 1WQ1, 2GQI, 2GSB, 2J05, 2J06

Identifiers

Symbols

RASA1; CM-AVM; CMAVM; DKFZp434N071; GAP; PKWS; RASA; RASGAP; p120GAP; p120RASGAP

External IDs

OMIM: 139150 MGI: 97860 HomoloGene: 2168 GeneCards: RASA1 Gene

Gene Ontology
Molecular function	• glycoprotein binding • Ras GTPase activator activity • receptor binding • protein binding • potassium channel inhibitor activity • GTPase binding
Cellular component	• ruffle • cytoplasm • cytoplasm • cytosol • plasma membrane • intrinsic to internal side of plasma membrane
Biological process	• cytokinesis • vasculogenesis • negative regulation of cell-matrix adhesion • negative regulation of cell adhesion • signal transduction • regulation of cell shape • embryo development • regulation of actin filament polymerization • positive regulation of Ras GTPase activity • positive regulation of Ras GTPase activity • intracellular signal transduction • negative regulation of neuron apoptosis • positive regulation of anti-apoptosis • negative regulation of Ras protein signal transduction • regulation of small GTPase mediated signal transduction • regulation of RNA metabolic process
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

n/a

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 5:
86.56 – 86.69 Mb

Chr 13:
85.35 – 85.43 Mb

PubMed search

[1]

[2]

RAS p21 protein activator 1 or RasGAP (Ras GTPase activating protein), also known as RASA1, is a 120-kDa cytosolic human protein that provides two principal activities:

Inactivation of Ras from its active GTP-bound form to its unactive GDP-bound form by enhancing the endogenous GTPase activity of Ras, via its C-terminal GAP domain
Mitogenic signal transmission towards downstream interacting partners through its N-terminal SH2-SH3-SH2 domains

The protein encoded by this gene is located in the cytoplasm and is part of the GAP1 family of GTPase-activating proteins. The gene product stimulates the GTPase activity of normal RAS p21 but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, thereby allowing control of cellular proliferation and differentiation. Mutations leading to changes in the binding sites of either protein are associated with basal cell carcinomas. Alternative splicing results in two isoforms where the shorter isoform, lacking the N-terminal hydrophobic region but retaining the same activity, appears to be abundantly expressed in placental but not adult tissues.^[1]

1 Domains
2 Interactions
3 Disease Database
4 External Links
5 References
6 Further reading

Domains

RasGAP contains one SH3 domain and two SH2 domains, a PH domain, and a GAP domain.

Interactions

RAS p21 protein activator 1 has been shown to interact with SOCS3,^[2] ANXA6,^[3] Huntingtin,^[4] KHDRBS1,^[5]^[6]^[7] Src,^[8]^[9] EPHB3,^[10] EPH receptor B2,^[11]^[12] Insulin-like growth factor 1 receptor,^[13] PTK2B,^[14]^[15] DOK1,^[16]^[17]^[18] PDGFRB,^[19]^[20] HCK,^[21] Caveolin 2,^[22] DNAJA3,^[23] HRAS^[9]^[24]^[25], GNB2L1 ^[26] and NCK1.^[27] The mRNA can interact with Mir-132 microRNA; this process is linked to angiogenesis.^[28]

Disease Database

RASA1 gene variant database

External Links

References

^ "Entrez Gene: RASA1 RAS p21 protein activator (GTPase activating protein) 1". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5921.
^ Cacalano, N A; Sanden D, Johnston J A (May. 2001). "Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras". Nat. Cell Biol. (England) 3 (5): 460–5. doi:10.1038/35074525. ISSN 1465-7392. PMID 11331873.
^ Chow, A; Gawler D (Oct. 1999). "Mapping the site of interaction between annexin VI and the p120GAP C2 domain". FEBS Lett. (NETHERLANDS) 460 (1): 166–72. doi:10.1016/S0014-5793(99)01336-8. ISSN 0014-5793. PMID 10571081.
^ Liu, Y F; Deth R C, Devys D (Mar. 1997). "SH3 domain-dependent association of huntingtin with epidermal growth factor receptor signaling complexes". J. Biol. Chem. (UNITED STATES) 272 (13): 8121–4. doi:10.1074/jbc.272.13.8121. ISSN 0021-9258. PMID 9079622.
^ Sánchez-Margalet, V; Najib S (Oct. 2001). "Sam68 is a docking protein linking GAP and PI3K in insulin receptor signaling". Mol. Cell. Endocrinol. (Ireland) 183 (1–2): 113–21. doi:10.1016/S0303-7207(01)00587-1. ISSN 0303-7207. PMID 11604231.
^ Jabado, N; Jauliac S, Pallier A, Bernard F, Fischer A, Hivroz C (Sep. 1998). "Sam68 association with p120GAP in CD4+ T cells is dependent on CD4 molecule expression". J. Immunol. (UNITED STATES) 161 (6): 2798–803. ISSN 0022-1767. PMID 9743338.
^ Koch, C A; Moran M F, Anderson D, Liu X Q, Mbamalu G, Pawson T (Mar. 1992). "Multiple SH2-mediated interactions in v-src-transformed cells". Mol. Cell. Biol. (UNITED STATES) 12 (3): 1366–74. ISSN 0270-7306. PMC 369570. PMID 1545818. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=369570.
^ Brott, B K; Decker S, O'Brien M C, Jove R (Oct. 1991). "Molecular features of the viral and cellular Src kinases involved in interactions with the GTPase-activating protein". Mol. Cell. Biol. (UNITED STATES) 11 (10): 5059–67. ISSN 0270-7306. PMC 361505. PMID 1717825. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=361505.
^ ^a ^b Giglione, C; Gonfloni S, Parmeggiani A (Jun. 2001). "Differential actions of p60c-Src and Lck kinases on the Ras regulators p120-GAP and GDP/GTP exchange factor CDC25Mm". Eur. J. Biochem. (Germany) 268 (11): 3275–83. doi:10.1046/j.1432-1327.2001.02230.x. ISSN 0014-2956. PMID 11389730.
^ Hock, B; Böhme B, Karn T, Feller S, Rübsamen-Waigmann H, Strebhardt K (Jul. 1998). "Tyrosine-614, the major autophosphorylation site of the receptor tyrosine kinase HEK2, functions as multi-docking site for SH2-domain mediated interactions". Oncogene (ENGLAND) 17 (2): 255–60. doi:10.1038/sj.onc.1201907. ISSN 0950-9232. PMID 9674711.
^ Holland, S J; Gale N W, Gish G D, Roth R A, Songyang Z, Cantley L C, Henkemeyer M, Yancopoulos G D, Pawson T (Jul. 1997). "Juxtamembrane tyrosine residues couple the Eph family receptor EphB2/Nuk to specific SH2 domain proteins in neuronal cells". EMBO J. (ENGLAND) 16 (13): 3877–88. doi:10.1093/emboj/16.13.3877. ISSN 0261-4189. PMC 1170012. PMID 9233798. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1170012.
^ Zisch, A H; Pazzagli C, Freeman A L, Schneller M, Hadman M, Smith J W, Ruoslahti E, Pasquale E B (Jan. 2000). "Replacing two conserved tyrosines of the EphB2 receptor with glutamic acid prevents binding of SH2 domains without abrogating kinase activity and biological responses". Oncogene (ENGLAND) 19 (2): 177–87. doi:10.1038/sj.onc.1203304. ISSN 0950-9232. PMID 10644995.
^ Seely, B L; Reichart D R, Staubs P A, Jhun B H, Hsu D, Maegawa H, Milarski K L, Saltiel A R, Olefsky J M (Aug. 1995). "Localization of the insulin-like growth factor I receptor binding sites for the SH2 domain proteins p85, Syp, and GTPase activating protein". J. Biol. Chem. (UNITED STATES) 270 (32): 19151–7. doi:10.1074/jbc.270.32.19151. ISSN 0021-9258. PMID 7642582.
^ Chow, A; Davis A J, Gawler D J (Mar. 2000). "Identification of a novel protein complex containing annexin VI, Fyn, Pyk2, and the p120(GAP) C2 domain". FEBS Lett. (NETHERLANDS) 469 (1): 88–92. doi:10.1016/S0014-5793(00)01252-7. ISSN 0014-5793. PMID 10708762.
^ Zrihan-Licht, S; Fu Y, Settleman J, Schinkmann K, Shaw L, Keydar I, Avraham S, Avraham H (Mar. 2000). "RAFTK/Pyk2 tyrosine kinase mediates the association of p190 RhoGAP with RasGAP and is involved in breast cancer cell invasion". Oncogene (ENGLAND) 19 (10): 1318–28. doi:10.1038/sj.onc.1203422. ISSN 0950-9232. PMID 10713673.
^ Dunant, N M; Wisniewski D, Strife A, Clarkson B, Resh M D (May. 2000). "The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 associates with the dok1 phosphoprotein in bcr-Abl transformed cells". Cell. Signal. (ENGLAND) 12 (5): 317–26. doi:10.1016/S0898-6568(00)00073-5. ISSN 0898-6568. PMID 10822173.
^ Yamanashi, Y; Baltimore D (Jan. 1997). "Identification of the Abl- and rasGAP-associated 62 kDa protein as a docking protein, Dok". Cell (UNITED STATES) 88 (2): 205–11. doi:10.1016/S0092-8674(00)81841-3. ISSN 0092-8674. PMID 9008161.
^ Némorin, J G; Duplay P (May. 2000). "Evidence that Llck-mediated phosphorylation of p56dok and p62dok may play a role in CD2 signaling". J. Biol. Chem. (UNITED STATES) 275 (19): 14590–7. doi:10.1074/jbc.275.19.14590. ISSN 0021-9258. PMID 10799545.
^ Farooqui, T; Kelley T, Coggeshall K M, Rampersaud A A, Yates A J (1999). "GM1 inhibits early signaling events mediated by PDGF receptor in cultured human glioma cells". Anticancer Res. (GREECE) 19 (6B): 5007–13. ISSN 0250-7005. PMID 10697503.
^ Ekman, Simon; Kallin Anders, Engström Ulla, Heldin Carl-Henrik, Rönnstrand Lars (Mar. 2002). "SHP-2 is involved in heterodimer specific loss of phosphorylation of Tyr771 in the PDGF beta-receptor". Oncogene (England) 21 (12): 1870–5. doi:10.1038/sj.onc.1205210. ISSN 0950-9232. PMID 11896619.
^ Briggs, S D; Bryant S S, Jove R, Sanderson S D, Smithgall T E (Jun. 1995). "The Ras GTPase-activating protein (GAP) is an SH3 domain-binding protein and substrate for the Src-related tyrosine kinase, Hck". J. Biol. Chem. (UNITED STATES) 270 (24): 14718–24. doi:10.1074/jbc.270.24.14718. ISSN 0021-9258. PMID 7782336.
^ Lee, Hyangkyu; Park David S, Wang Xiao Bo, Scherer Philipp E, Schwartz Phillip E, Lisanti Michael P (Sep. 2002). "Src-induced phosphorylation of caveolin-2 on tyrosine 19. Phospho-caveolin-2 (Tyr(P)19) is localized near focal adhesions, remains associated with lipid rafts/caveolae, but no longer forms a high molecular mass hetero-oligomer with caveolin-1". J. Biol. Chem. (United States) 277 (37): 34556–67. doi:10.1074/jbc.M204367200. ISSN 0021-9258. PMID 12091389.
^ Trentin, G A; Yin X, Tahir S, Lhotak S, Farhang-Fallah J, Li Y, Rozakis-Adcock M (Apr. 2001). "A mouse homologue of the Drosophila tumor suppressor l(2)tid gene defines a novel Ras GTPase-activating protein (RasGAP)-binding protein". J. Biol. Chem. (United States) 276 (16): 13087–95. doi:10.1074/jbc.M009267200. ISSN 0021-9258. PMID 11116152.
^ Molloy, D P; Owen D, Grand R J (Jul. 1995). "Ras binding to a C-terminal region of GAP". FEBS Lett. (NETHERLANDS) 368 (2): 297–303. doi:10.1016/0014-5793(95)00657-U. ISSN 0014-5793. PMID 7628625.
^ Scheffzek, K; Ahmadian M R, Kabsch W, Wiesmüller L, Lautwein A, Schmitz F, Wittinghofer A (Jul. 1997). "The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants". Science (UNITED STATES) 277 (5324): 333–8. doi:10.1126/science.277.5324.333. ISSN 0036-8075. PMID 9219684.
^ Koehler, J A; Moran M F (May. 2001). "RACK1, a protein kinase C scaffolding protein, interacts with the PH domain of p120GAP". Biochem. Biophys. Res. Commun. (United States) 283 (4): 888–95. doi:10.1006/bbrc.2001.4889. ISSN 0006-291X. PMID 11350068.
^ Ger, M; Zitkus Z, Valius M (Oct. 2011). "Adaptor protein Nck1 interacts with p120 Ras GTPase-activating protein and regulates its activity". Cell. Signal. (ENGLAND) 23 (10): 1651–8. doi:10.1016/j.cellsig.2011.05.019. ISSN 0898-6568. PMID 21664272.
^ Anand S, Majeti BK, Acevedo LM, Murphy EA, Mukthavaram R, Scheppke L, Huang M, Shields DJ, Lindquist JN, Lapinski PE, King PD, Weis SM, Cheresh DA (2010). "MicroRNA-132–mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis". Nat Med 16 (8): 909–14. doi:10.1038/nm.2186. PMC 3094020. PMID 20676106. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3094020.