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RAS p21 protein activator 1

From Wikipedia, the free encyclopedia

RASA1
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesRASA1,CM-AVM, CMAVM, GAP, PKWS, RASA, RASGAP, p120GAP, p120RASGAP, RAS p21 protein activator 1, p120, CMAVM1
External IDsOMIM:139150;MGI:97860;HomoloGene:2168;GeneCards:RASA1;OMA:RASA1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5921

218397

Ensembl

ENSG00000145715

ENSMUSG00000021549

UniProt

P20936

E9PYG6

RefSeq (mRNA)

NM_002890
NM_022650

NM_145452

RefSeq (protein)

NP_002881
NP_072179

NP_663427

Location (UCSC)Chr 5: 87.27 – 87.39 MbChr 13: 85.36 – 85.44 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

RAS p21 protein activator 1orRasGAP(Ras GTPase activating protein), also known asRASA1,is a 120-kDacytosolic human protein that provides two principal activities:

  • Inactivation ofRasfrom its activeGTP-bound form to its inactiveGDP-bound form by enhancing the endogenousGTPaseactivity 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.[5]

Domains

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RasGAP contains oneSH3 domainand twoSH2 domains,aPH domain,a C2 domain, and aGAP domain.

Interactions

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RAS p21 protein activator 1 has been shown tointeractwith:

The mRNA can interact withMir-132 microRNA;this process is linked to angiogenesis.[32]

Disease database

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RASA1 gene variant database

References

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  1. ^abcGRCh38: Ensembl release 89: ENSG00000145715–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000021549–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^"Entrez Gene: RASA1 RAS p21 protein activator (GTPase activating protein) 1".
  6. ^Chow A, Gawler D (October 1999). "Mapping the site of interaction between annexin VI and the p120GAP C2 domain".FEBS Lett.460(1): 166–72.doi:10.1016/s0014-5793(99)01336-8.PMID10571081.S2CID42114086.
  7. ^Lee H, Park DS, Wang XB, Scherer PE, Schwartz PE, Lisanti MP (September 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.277(37): 34556–67.doi:10.1074/jbc.M204367200.PMID12091389.
  8. ^Trentin GA, Yin X, Tahir S, Lhotak S, Farhang-Fallah J, Li Y, Rozakis-Adcock M (April 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.276(16): 13087–95.doi:10.1074/jbc.M009267200.PMID11116152.
  9. ^Dunant NM, Wisniewski D, Strife A, Clarkson B, Resh MD (May 2000). "The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 associates with the dok1 phosphoprotein in bcr-Abl transformed cells".Cell. Signal.12(5): 317–26.doi:10.1016/s0898-6568(00)00073-5.PMID10822173.
  10. ^Yamanashi Y, Baltimore D (January 1997)."Identification of the Abl- and rasGAP-associated 62 kDa protein as a docking protein, Dok".Cell.88(2): 205–11.doi:10.1016/s0092-8674(00)81841-3.PMID9008161.S2CID14205526.
  11. ^Némorin JG, Duplay P (May 2000)."Evidence that Llck-mediated phosphorylation of p56dok and p62dok may play a role in CD2 signaling".J. Biol. Chem.275(19): 14590–7.doi:10.1074/jbc.275.19.14590.PMID10799545.
  12. ^Holland SJ, Gale NW, Gish GD, Roth RA, Songyang Z, Cantley LC, Henkemeyer M, Yancopoulos GD, Pawson T (July 1997)."Juxtamembrane tyrosine residues couple the Eph family receptor EphB2/Nuk to specific SH2 domain proteins in neuronal cells".EMBO J.16(13): 3877–88.doi:10.1093/emboj/16.13.3877.PMC1170012.PMID9233798.
  13. ^Zisch AH, Pazzagli C, Freeman AL, Schneller M, Hadman M, Smith JW, Ruoslahti E, Pasquale EB (January 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.19(2): 177–87.doi:10.1038/sj.onc.1203304.PMID10644995.S2CID21872001.
  14. ^Hock B, Böhme B, Karn T, Feller S, Rübsamen-Waigmann H, Strebhardt K (July 1998). "Tyrosine-614, the major autophosphorylation site of the receptor tyrosine kinase HEK2, functions as multi-docking site for SH2-domain mediated interactions".Oncogene.17(2): 255–60.doi:10.1038/sj.onc.1201907.PMID9674711.S2CID25714553.
  15. ^Koehler JA, Moran MF (May 2001). "RACK1, a protein kinase C scaffolding protein, interacts with the PH domain of p120GAP".Biochem. Biophys. Res. Commun.283(4): 888–95.doi:10.1006/bbrc.2001.4889.PMID11350068.
  16. ^Briggs SD, Bryant SS, Jove R, Sanderson SD, Smithgall TE (June 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.270(24): 14718–24.doi:10.1074/jbc.270.24.14718.PMID7782336.
  17. ^abGiglione C, Gonfloni S, Parmeggiani A (June 2001). "Differential actions of p60c-Src and Lck kinases on the Ras regulators p120-GAP and GDP/GTP exchange factor CDC25Mm".Eur. J. Biochem.268(11): 3275–83.doi:10.1046/j.1432-1327.2001.02230.x.PMID11389730.
  18. ^Molloy DP, Owen D, Grand RJ (July 1995)."Ras binding to a C-terminal region of GAP".FEBS Lett.368(2): 297–303.doi:10.1016/0014-5793(95)00657-u.PMID7628625.S2CID23151818.
  19. ^Sprang SR (July 1997). "GAP into the breach".Science.277(5324): 329–30.doi:10.1126/science.277.5324.329.PMID9518363.S2CID22836050.
  20. ^Liu YF, Deth RC, Devys D (March 1997)."SH3 domain-dependent association of huntingtin with epidermal growth factor receptor signaling complexes".J. Biol. Chem.272(13): 8121–4.doi:10.1074/jbc.272.13.8121.PMID9079622.
  21. ^Seely BL, Reichart DR, Staubs PA, Jhun BH, Hsu D, Maegawa H, Milarski KL, Saltiel AR, Olefsky JM (August 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.270(32): 19151–7.doi:10.1074/jbc.270.32.19151.PMID7642582.
  22. ^Sánchez-Margalet V, Najib S (October 2001). "Sam68 is a docking protein linking GAP and PI3K in insulin receptor signaling".Mol. Cell. Endocrinol.183(1–2): 113–21.doi:10.1016/s0303-7207(01)00587-1.PMID11604231.S2CID24594450.
  23. ^Jabado N, Jauliac S, Pallier A, Bernard F, Fischer A, Hivroz C (September 1998)."Sam68 association with p120GAP in CD4+ T cells is dependent on CD4 molecule expression".J. Immunol.161(6): 2798–803.doi:10.4049/jimmunol.161.6.2798.PMID9743338.S2CID10463909.
  24. ^Koch CA, Moran MF, Anderson D, Liu XQ, Mbamalu G, Pawson T (March 1992)."Multiple SH2-mediated interactions in v-src-transformed cells".Mol. Cell. Biol.12(3): 1366–74.doi:10.1128/mcb.12.3.1366.PMC369570.PMID1545818.
  25. ^Ger M, Zitkus Z, Valius M (October 2011). "Adaptor protein Nck1 interacts with p120 Ras GTPase-activating protein and regulates its activity".Cell. Signal.23(10): 1651–8.doi:10.1016/j.cellsig.2011.05.019.PMID21664272.
  26. ^Farooqui T, Kelley T, Coggeshall KM, Rampersaud AA, Yates AJ (1999). "GM1 inhibits early signaling events mediated by PDGF receptor in cultured human glioma cells".Anticancer Res.19(6B): 5007–13.PMID10697503.
  27. ^Ekman S, Kallin A, Engström U, Heldin CH, Rönnstrand L (March 2002). "SHP-2 is involved in heterodimer specific loss of phosphorylation of Tyr771 in the PDGF beta-receptor".Oncogene.21(12): 1870–5.doi:10.1038/sj.onc.1205210.PMID11896619.S2CID35823546.
  28. ^Chow A, Davis AJ, Gawler DJ (March 2000)."Identification of a novel protein complex containing annexin VI, Fyn, Pyk2, and the p120(GAP) C2 domain".FEBS Lett.469(1): 88–92.doi:10.1016/s0014-5793(00)01252-7.PMID10708762.S2CID21394463.
  29. ^Zrihan-Licht S, Fu Y, Settleman J, Schinkmann K, Shaw L, Keydar I, Avraham S, Avraham H (March 2000)."RAFTK/Pyk2 tyrosine kinase mediates the association of p190 RhoGAP with RasGAP and is involved in breast cancer cell invasion".Oncogene.19(10): 1318–28.doi:10.1038/sj.onc.1203422.PMID10713673.
  30. ^Cacalano NA, Sanden D, Johnston JA (May 2001). "Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras".Nat. Cell Biol.3(5): 460–5.doi:10.1038/35074525.PMID11331873.S2CID19179597.
  31. ^Brott BK, Decker S, O'Brien MC, Jove R (October 1991)."Molecular features of the viral and cellular Src kinases involved in interactions with the GTPase-activating protein".Mol. Cell. Biol.11(10): 5059–67.doi:10.1128/mcb.11.10.5059.PMC361505.PMID1717825.
  32. ^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.PMC3094020.PMID20676106.

Further reading

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