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- Ras GTPase-activating protein
Wikipedia preview
出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2012/10/21 00:22:14」(JST)
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RAS p21 protein activator (GTPase activating protein) 1 |
PDB rendering based on 1wer. |
Available structures |
PDB |
Ortholog search: PDBe, RCSB |
List of PDB id codes |
1WER, 1WQ1, 2GQI, 2GSB, 2J05, 2J06, 4FSS
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Identifiers |
Symbols |
RASA1; CM-AVM; CMAVM; 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
• phospholipid binding
• potassium channel inhibitor activity
• GTPase binding
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Cellular component |
• ruffle
• cytoplasm
• cytosol
• intrinsic to internal side of plasma membrane
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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
• intracellular signal transduction
• negative regulation of neuron apoptotic process
• positive regulation of anti-apoptosis
• negative regulation of Ras protein signal transduction
• regulation of RNA metabolic process
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Sources: Amigo / QuickGO |
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RNA expression pattern |
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More reference expression data |
Orthologs |
Species |
Human |
Mouse |
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Entrez |
5921 |
218397 |
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Ensembl |
ENSG00000145715 |
ENSMUSG00000021549 |
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UniProt |
P20936 |
E9PYG6 |
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RefSeq (mRNA) |
NM_002890.2 |
NM_145452.3 |
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RefSeq (protein) |
NP_002881.1 |
NP_663427.2 |
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Location (UCSC) |
Chr 5:
86.56 – 86.69 Mb |
Chr 13:
85.21 – 85.29 Mb |
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PubMed search |
[1] |
[2] |
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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]
Contents
- 1 Domains
- 2 Interactions
- 3 Disease Database
- 4 References
- 5 External links
- 6 Further reading
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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
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 (October 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 (March 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 (October 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 (September 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 (March 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC369570/.
- ^ Brott, B K; Decker S, O'Brien M C, Jove R (October 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC361505/.
- ^ a b Giglione, 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. (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 (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 (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 (July 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1170012/.
- ^ Zisch, A H; Pazzagli C, Freeman A L, Schneller M, Hadman M, Smith J W, Ruoslahti E, Pasquale E B (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 (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 (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. (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 (March 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 (March 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 (January 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 (March 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 (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. (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 (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. (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 (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. (United States) 276 (16): 13087–95. doi:10.1074/jbc.M009267200. ISSN 0021-9258. PMID 11116152.
- ^ Molloy, D P; Owen D, Grand R J (July 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 (July 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 9518363.
- ^ 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 (October 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3094020/.
External links
- GeneReviews/NCBI/NIH/UW entry on Capillary Malformation-Arteriovenous Malformation Syndrome and RASA1-Related Parkes Weber Syndrome
- OMIM entries in RASA1 related disorders
Further reading
- Tocque B, Delumeau I, Parker F, et al. (1997). "Ras-GTPase activating protein (GAP): a putative effector for Ras". Cell. Signal. 9 (2): 153–8. doi:10.1016/S0898-6568(96)00135-0. PMID 9113414.
- Boon LM, Mulliken JB, Vikkula M (2005). "RASA1: variable phenotype with capillary and arteriovenous malformations". Curr. Opin. Genet. Dev. 15 (3): 265–9. doi:10.1016/j.gde.2005.03.004. PMID 15917201.
PDB gallery
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1wer: RAS-GTPASE-ACTIVATING DOMAIN OF HUMAN P120GAP
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2gqi: Solution structure of the SH3 domain of human Ras GTPase-activating protein 1
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2gsb: Solution structure of the second SH2 domain of human Ras GTPase-activating protein 1
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2j05: CRYSTAL STRUCTURE OF THE RASGAP SH3 DOMAIN AT 1.5 ANGSTROM RESOLUTION
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2j06: CRYSTAL STRUCTURE OF THE RASGAP SH3 DOMAIN AT 1.8 ANGSTROM RESOLUTION
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GTP-binding protein regulators
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GTPase activating protein |
Monomeric
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Chimerin (CHN1, CHN2) · RasGAP (NF1, IQGAP) · Tuberous sclerosis protein (TSC1, TSC2)
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Heterotrimeric
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Regulator of G protein signalling: RGS1, RGS2, RGS3, RGS4, RGS5, RGS6, RGS7, RGS8, RGS9, RGS10, RGS11, RGS12, RGS13, RGS14, RGS16, RGS17, RGS18, RGS19, RGS20, RGS21
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Guanine nucleotide exchange factor |
EIF2B · Son of Sevenless · Ras-GRF1
FGD: FGD1 · FGD2 · FGD3 · FGD4
ALS2 · SIL1 · IQSEC2
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Other |
Guanosine nucleotide dissociation inhibitors
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B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)
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English Journal
- Phosphoprotein associated with glycosphingolipid microdomains 1 inhibits the proliferation and invasion of human prostate cancer cells in vitro through suppression of Ras activation.
- Yu W, Wang Y, Gong M, Pei F, Zheng J.SourceDepartment of Pathology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, P.R. China.
- Oncology reports.Oncol Rep.2012 Aug;28(2):606-14. doi: 10.3892/or.2012.1848. Epub 2012 Jun 1.
- Phosphoprotein associated with glycosphingolipid microdomains 1 (PAG) is an important negative regulator of immune signaling in T lymphocytes. However, newly emerging evidence has indicated that PAG may play important roles in tumor cells. Our previously reported
- PMID 22664862
- Phosphotyrosine mediated protein interactions of the discoidin domain receptor 1.
- Lemeer S, Bluwstein A, Wu Z, Leberfinger J, Müller K, Kramer K, Kuster B.SourceChair of Proteomics and Bioanalytics, Technische Universität München, Emil Erlenmeyer Forum 5, 85354 Freising, Germany.
- Journal of proteomics.J Proteomics.2012 Jun 27;75(12):3465-77. Epub 2011 Oct 26.
- The receptor tyrosine kinase DDR1 has been implicated in multiple human cancers and fibrosis and is targeted by the leukemia drug Gleevec. This suggests that DDR1 might be a new therapeutic target. However, further insight into the DDR1 signaling pathway is required in order to support its further d
- PMID 22057045
Japanese Journal
- The kelch proteins Gpb1 and Gpb2 inhibit Ras activity via association with the yeast RasGAP neurofibromin homologs Ira1 and Ira2
- The rasGAP-binding protein, Dok-1, mediates activin signaling via serine/threonine kinase receptors
Related Links
- 1. Science. 1997 Jul 18;277(5324):333-8. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Scheffzek K(1), Ahmadian MR, Kabsch W, Wiesmüller L, Lautwein A, Schmitz F ...
- p120-RasGAP (Ras GTPase activating protein) plays a key role in the regulation of Ras-GTP bound by promoting GTP hydrolysis via its C-terminal catalytic domain. ... Fig. 1. Schematic representation of Ras cycle and RasGAP ...
★リンクテーブル★
[★]
Ras-GTPase活性化タンパク質
- 関
- RasGAP
[★]
- 英
- Ras GTPase-activating protein、RasGAP