RAS p21 protein activator 1 explained

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 inactive 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]

Domains

RasGAP contains one SH3 domain and two SH2 domains, a PH domain, a C2 domain, and a GAP domain.

Interactions

RAS p21 protein activator 1 has been shown to interact with:

• ANXA6,^[2]
• CAV2,^[3]
• DNAJA3,^[4]
• DOK1,^{[5] [6] [7]}
• EPHB2,^{[8] [9]}
• EPHB3,^[10]
• GNB2L1^[11]
• HCK,^[12]
• HRAS,^{[13] [14]}
• HTT,^[15]
• IGF1R,^[16]
• KHDRBS1,^{[17] [18] [19]}
• NCK1,^[20]
• PDGFRB,^{[21] [22]}
• PTK2B,^{[23] [24]}
• SOCS3,^[25] and
• Src.^{[26] [27]}

The mRNA can interact with Mir-132 microRNA; this process is linked to angiogenesis.^[28]

Disease database

RASA1 gene variant database

Further reading

• Tocque B, Delumeau I, Parker F, etal . Ras-GTPase activating protein (GAP): a putative effector for Ras . Cell. Signal. . 9 . 2 . 153–8 . 1997 . 9113414 . 10.1016/S0898-6568(96)00135-0 .
• Boon LM, Mulliken JB, Vikkula M . RASA1: variable phenotype with capillary and arteriovenous malformations . Curr. Opin. Genet. Dev. . 15 . 3 . 265–9 . 2005 . 15917201 . 10.1016/j.gde.2005.03.004 .

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

Notes and References

1. Web site: Entrez Gene: RASA1 RAS p21 protein activator (GTPase activating protein) 1.
2. October 1999 . Chow A, Gawler D . Mapping the site of interaction between annexin VI and the p120GAP C2 domain . FEBS Lett. . 460 . 1 . 166–72 . 10571081 . 10.1016/s0014-5793(99)01336-8. 42114086 .
3. September 2002 . Lee H, Park DS, Wang XB, Scherer PE, Schwartz PE, Lisanti MP . 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 . 12091389 . 10.1074/jbc.M204367200. free.
4. April 2001 . Trentin GA, Yin X, Tahir S, Lhotak S, Farhang-Fallah J, Li Y, Rozakis-Adcock M . 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 . 11116152 . 10.1074/jbc.M009267200. free .
5. May 2000 . Dunant NM, Wisniewski D, Strife A, Clarkson B, Resh MD . The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 associates with the dok1 phosphoprotein in bcr-Abl transformed cells . Cell. Signal. . 12 . 5 . 317–26 . 10822173 . 10.1016/s0898-6568(00)00073-5.
6. January 1997 . Yamanashi Y, Baltimore D . Identification of the Abl- and rasGAP-associated 62 kDa protein as a docking protein, Dok . Cell . 88 . 2 . 205–11 . 9008161 . 10.1016/s0092-8674(00)81841-3. 14205526 . free .
7. May 2000 . Némorin JG, Duplay P . Evidence that Llck-mediated phosphorylation of p56dok and p62dok may play a role in CD2 signaling . J. Biol. Chem. . 275 . 19 . 14590–7 . 10799545 . 10.1074/jbc.275.19.14590. free .
8. July 1997 . Holland SJ, Gale NW, Gish GD, Roth RA, Songyang Z, Cantley LC, Henkemeyer M, Yancopoulos GD, Pawson T . Juxtamembrane tyrosine residues couple the Eph family receptor EphB2/Nuk to specific SH2 domain proteins in neuronal cells . EMBO J. . 16 . 13 . 3877–88 . 9233798 . 1170012 . 10.1093/emboj/16.13.3877.
9. January 2000 . Zisch AH, Pazzagli C, Freeman AL, Schneller M, Hadman M, Smith JW, Ruoslahti E, Pasquale EB . 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 . 10644995 . 10.1038/sj.onc.1203304. 21872001 .
10. July 1998 . Hock B, Böhme B, Karn T, Feller S, Rübsamen-Waigmann H, Strebhardt K . 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 . 9674711 . 10.1038/sj.onc.1201907. 25714553 .
11. May 2001 . Koehler JA, Moran MF . RACK1, a protein kinase C scaffolding protein, interacts with the PH domain of p120GAP . Biochem. Biophys. Res. Commun. . 283 . 4 . 888–95 . 11350068 . 10.1006/bbrc.2001.4889.
12. June 1995 . Briggs SD, Bryant SS, Jove R, Sanderson SD, Smithgall TE . 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 . 7782336 . 10.1074/jbc.270.24.14718. free.
13. July 1995 . Molloy DP, Owen D, Grand RJ . Ras binding to a C-terminal region of GAP . FEBS Lett. . 368 . 2 . 297–303 . 7628625 . 10.1016/0014-5793(95)00657-u. 23151818 . free .
14. July 1997 . Sprang SR . GAP into the breach . Science . 277 . 5324 . 329–30 . 9518363 . 10.1126/science.277.5324.329. 22836050 .
15. March 1997 . Liu YF, Deth RC, Devys D . SH3 domain-dependent association of huntingtin with epidermal growth factor receptor signaling complexes . J. Biol. Chem. . 272 . 13 . 8121–4 . 9079622 . 10.1074/jbc.272.13.8121. free .
16. August 1995 . Seely BL, Reichart DR, Staubs PA, Jhun BH, Hsu D, Maegawa H, Milarski KL, Saltiel AR, Olefsky JM . 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 . 7642582 . 10.1074/jbc.270.32.19151. free.
17. October 2001 . Sánchez-Margalet V, Najib S . Sam68 is a docking protein linking GAP and PI3K in insulin receptor signaling . Mol. Cell. Endocrinol. . 183 . 1–2 . 113–21 . 11604231 . 10.1016/s0303-7207(01)00587-1. 24594450 .
18. September 1998 . Jabado N, Jauliac S, Pallier A, Bernard F, Fischer A, Hivroz C . Sam68 association with p120GAP in CD4+ T cells is dependent on CD4 molecule expression . J. Immunol. . 161 . 6 . 2798–803 . 10.4049/jimmunol.161.6.2798 . 9743338 . 10463909 . free .
19. March 1992 . Koch CA, Moran MF, Anderson D, Liu XQ, Mbamalu G, Pawson T . Multiple SH2-mediated interactions in v-src-transformed cells . Mol. Cell. Biol. . 12 . 3 . 1366–74 . 1545818 . 369570 . 10.1128/mcb.12.3.1366.
20. October 2011 . Ger M, Zitkus Z, Valius M . Adaptor protein Nck1 interacts with p120 Ras GTPase-activating protein and regulates its activity . Cell. Signal. . 23 . 10 . 1651–8 . 21664272 . 10.1016/j.cellsig.2011.05.019.
21. Farooqui T, Kelley T, Coggeshall KM, Rampersaud AA, Yates AJ . GM1 inhibits early signaling events mediated by PDGF receptor in cultured human glioma cells . Anticancer Res. . 19 . 6B . 5007–13 . 10697503 . 1999.
22. March 2002 . Ekman S, Kallin A, Engström U, Heldin CH, Rönnstrand L . SHP-2 is involved in heterodimer specific loss of phosphorylation of Tyr771 in the PDGF beta-receptor . Oncogene . 21 . 12 . 1870–5 . 11896619 . 10.1038/sj.onc.1205210. 35823546 .
23. March 2000 . Chow A, Davis AJ, Gawler DJ . Identification of a novel protein complex containing annexin VI, Fyn, Pyk2, and the p120(GAP) C2 domain . FEBS Lett. . 469 . 1 . 88–92 . 10708762 . 10.1016/s0014-5793(00)01252-7. 21394463 . free .
24. March 2000 . Zrihan-Licht S, Fu Y, Settleman J, Schinkmann K, Shaw L, Keydar I, Avraham S, Avraham H . 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 . 10713673 . 10.1038/sj.onc.1203422. free .
25. May 2001 . Cacalano NA, Sanden D, Johnston JA . Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras . Nat. Cell Biol. . 3 . 5 . 460–5 . 11331873 . 10.1038/35074525. 19179597 .
26. June 2001 . Giglione C, Gonfloni S, Parmeggiani A . 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 . 11389730 . 10.1046/j.1432-1327.2001.02230.x.
27. October 1991 . Brott BK, Decker S, O'Brien MC, Jove R . Molecular features of the viral and cellular Src kinases involved in interactions with the GTPase-activating protein . Mol. Cell. Biol. . 11 . 10 . 5059–67 . 1717825 . 361505 . 10.1128/mcb.11.10.5059.
28. 10.1038/nm.2186 . 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 . MicroRNA-132–mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis . Nat Med . 16 . 8 . 909–14 . 2010 . 20676106 . 3094020.