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Rasa1  -  RAS p21 protein activator 1

Mus musculus

Synonyms: Gap, RasGAP, Rasa, p120-rasGAP
 
 
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Disease relevance of Rasa1

  • We purified Gap b3 (one of the Gap b group) to homogeneity from hamster fibroblast NIL cells transformed with polyoma virus (NILpy) [1].
  • INTRODUCTION: Gap junction channels are important determinants of conduction in the heart and may play a central role in the development of lethal cardiac arrhythmias [2].
 

High impact information on Rasa1

 

Biological context of Rasa1

  • Our results suggest that p120-Gap has specific functions in downregulating the Ras/MAP kinase pathway following growth factor stimulation, and in modulating the phosphorylation of p190-rhoGap, but is not required for mitogenic signalling [6].
  • Induction of DNA synthesis in response to platelet-derived growth factor and morphological transformation by the v-src and EJ-ras oncogenes were not significantly affected by the absence of p120-Gap [6].
  • These GAPs possess a common catalytic domain but contain distinct regulatory elements that may couple different external signals to control of the Ras pathway. p120-Gap, for example, has two N-terminal SH2 domains that directly recognize phosphotyrosine motifs on activated growth factor receptors and cytoplasmic phosphoproteins [6].
  • EGF-induced actin stress fiber disassembly and reassembly occurred with the same kinetics and frequency as did p190 and RasGAP rearrangements in all three cell lines [7].
  • We have now determined the contribution of this second cleavage event in the regulation of apoptosis using cells in which the wild-type RasGAP gene has been replaced by a cDNA encoding a RasGAP mutant that cannot be cleaved at position 157 [8].
 

Anatomical context of Rasa1

 

Physical interactions of Rasa1

  • Moreover, Gab1 was found to interact with RasGAP SH2 domains, only under conditions where SHP2 is not activated [12].
 

Regulatory relationships of Rasa1

  • p190 RhoGAP is a tyrosine phosphorylated protein that contains an N-terminal GTP binding domain, a middle domain (MD) that mediates interaction with p120 RasGAP and a C-terminal GTPase-activating protein (GAP) domain that is specific for the &Rgr; family of small GTPases [13].
  • We observed that a Gab1 construct preventing SHP2 recruitment promoted membrane relocation of RasGAP [12].
 

Other interactions of Rasa1

  • p190 RhoGAP is a 190-kDa protein that stably associates with p120 RasGAP and regulates actin dynamics through members of the Rho family of small GTPases [14].
  • When caspase-3 is mildly activated, RasGAP is first cleaved at position 455 [8].
  • Therefore, the role of the second caspase-mediated cleavage of RasGAP is to allow the inactivation of the antiapoptotic function of fragment N so that caspases are no longer hampered in their ability to kill cells [8].
  • The deletion suppressed RasGAP redistribution and restored the defective Ras activation caused by SHP2-inactivating mutations [12].
  • To determine whether Gab1 is a RasGAP-binding partner, a Gab1 mutant deleted of four YXXP motifs was produced [12].

References

  1. Characterization through cDNA cloning of galactoprotein b3 (Gap b3), a cell surface membrane glycoprotein showing enhanced expression on oncogenic transformation. Identification of Gap b3 as a member of the integrin superfamily. Tsuji, T., Yamamoto, F., Miura, Y., Takio, K., Titani, K., Pawar, S., Osawa, T., Hakomori, S. J. Biol. Chem. (1990) [Pubmed]
  2. Characterization of conduction in the ventricles of normal and heterozygous Cx43 knockout mice using optical mapping. Morley, G.E., Vaidya, D., Samie, F.H., Lo, C., Delmar, M., Jalife, J. J. Cardiovasc. Electrophysiol. (1999) [Pubmed]
  3. Vascular system defects and neuronal apoptosis in mice lacking ras GTPase-activating protein. Henkemeyer, M., Rossi, D.J., Holmyard, D.P., Puri, M.C., Mbamalu, G., Harpal, K., Shih, T.S., Jacks, T., Pawson, T. Nature (1995) [Pubmed]
  4. The RasGAP-binding protein p62dok is a mediator of inhibitory FcgammaRIIB signals in B cells. Tamir, I., Stolpa, J.C., Helgason, C.D., Nakamura, K., Bruhns, P., Daeron, M., Cambier, J.C. Immunity (2000) [Pubmed]
  5. Dok-related protein negatively regulates T cell development via its RasGTPase-activating protein and Nck docking sites. Gugasyan, R., Quilici, C., I, S.T., Grail, D., Verhagen, A.M., Roberts, A., Kitamura, T., Dunn, A.R., Lock, P. J. Cell Biol. (2002) [Pubmed]
  6. Aberrant Ras regulation and reduced p190 tyrosine phosphorylation in cells lacking p120-Gap. van der Geer, P., Henkemeyer, M., Jacks, T., Pawson, T. Mol. Cell. Biol. (1997) [Pubmed]
  7. c-Src regulates the simultaneous rearrangement of actin cytoskeleton, p190RhoGAP, and p120RasGAP following epidermal growth factor stimulation. Chang, J.H., Gill, S., Settleman, J., Parsons, S.J. J. Cell Biol. (1995) [Pubmed]
  8. Impaired Akt activity down-modulation, caspase-3 activation, and apoptosis in cells expressing a caspase-resistant mutant of RasGAP at position 157. Yang, J.Y., Walicki, J., Michod, D., Dubuis, G., Widmann, C. Mol. Biol. Cell (2005) [Pubmed]
  9. Downstream of kinase, p62(dok), is a mediator of Fc gamma IIB inhibition of Fc epsilon RI signaling. Ott, V.L., Tamir, I., Niki, M., Pandolfi, P.P., Cambier, J.C. J. Immunol. (2002) [Pubmed]
  10. RasGAP-associated endoribonuclease G3Bp: selective RNA degradation and phosphorylation-dependent localization. Tourrière, H., Gallouzi, I.E., Chebli, K., Capony, J.P., Mouaikel, J., van der Geer, P., Tazi, J. Mol. Cell. Biol. (2001) [Pubmed]
  11. Protein Kinase A-mediated Phosphorylation of Connexin36 in Mouse Retina Results in Decreased Gap Junctional Communication between AII Amacrine Cells. Urschel, S., H??her, T., Schubert, T., Alev, C., S??hl, G., W??rsd??rfer, P., Asahara, T., Dermietzel, R., Weiler, R., Willecke, K. J. Biol. Chem. (2006) [Pubmed]
  12. A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation. Montagner, A., Yart, A., Dance, M., Perret, B., Salles, J.P., Raynal, P. J. Biol. Chem. (2005) [Pubmed]
  13. Phosphorylation of p190 on Tyr1105 by c-Src is necessary but not sufficient for EGF-induced actin disassembly in C3H10T1/2 fibroblasts. Haskell, M.D., Nickles, A.L., Agati, J.M., Su, L., Dukes, B.D., Parsons, S.J. J. Cell. Sci. (2001) [Pubmed]
  14. Phosphotyrosine (p-Tyr)-dependent and -independent mechanisms of p190 RhoGAP-p120 RasGAP interaction: Tyr 1105 of p190, a substrate for c-Src, is the sole p-Tyr mediator of complex formation. Roof, R.W., Haskell, M.D., Dukes, B.D., Sherman, N., Kinter, M., Parsons, S.J. Mol. Cell. Biol. (1998) [Pubmed]
 
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