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Gene Review

ARHGAP35  -  Rho GTPase activating protein 35

Homo sapiens

Synonyms: GRF-1, GRF1, GRLF1, Glucocorticoid receptor DNA-binding factor 1, Glucocorticoid receptor repression factor 1, ...
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Disease relevance of GRLF1

  • These data suggest that the inhibitory action of p190 RhoGAP toward RhoA offers a novel approach to the treatment of invasion and metastasis of cancer cells [1].
  • Inactivation of Rho GTPases by p190 RhoGAP reduces human pancreatic cancer cell invasion and metastasis [1].
  • p190-A, a human tumor suppressor gene, maps to the chromosomal region 19q13.3 that is reportedly deleted in some gliomas [2].
  • Moreover, at least 40% glioblastoma/astrocytoma cases with breakpoints in this region were previously reported to show loss of the chromosomal region encompassing p190-A, suggesting the possibility that loss or mutations of this gene might be in part responsible for the development of these tumors [2].
  • The gene encoding p190RhoGAP is located at 19q13.3 of the human chromosome, a locus that is deleted in 50%-80% of oligodendrogliomas [3].

High impact information on GRLF1


Biological context of GRLF1


Anatomical context of GRLF1

  • Thus, in neutrophils, beta(2) integrin-induced activation of p190RhoGAP requires a signal from a Src family tyrosine kinase, but it does not occur via the signaling pathway responsible for activation of RHOA:[10]
  • We have previously demonstrated, using rat p190-A cDNA, that full-length p190-A is a tumor suppressor, reversing v-Ha-Ras-induced malignancy of NIH 3T3 cells through both the N-terminal GTPase (residues 1-251) and the C-terminal Rho GAP (residues 1168-1441) domains [2].
  • Integrin-mediated adhesion promotes relocalization of p190 and p120 to the cell periphery in wild-type fibroblasts, but not in arg(-/-) fibroblasts [11].
  • Transforming growth factor beta regulates the expression of the M2 muscarinic receptor in atrial myocytes via an effect on RhoA and p190RhoGAP [12].
  • Subsequently, through alpha5beta1 integrin, heparan sulfate, and lipid raft-mediated interactions, endostatin induced Src-dependent activation of p190RhoGAP with concomitant decrease in RhoA activity and disassembly of actin stress fibers and focal adhesions [13].

Associations of GRLF1 with chemical compounds

  • The activity of the RhoA inhibitor p190RhoGAP is decreased due to its serine/threonine phosphorylation at this time [14].
  • Furthermore, levels of endogenous p190 protein were transiently decreased in late mitosis via an ubiquitin-mediated degradation process that required the NH2-terminal GTP-binding region of p190 [15].
  • By screening for genes expressed differentially in pancreatic beta cells, we have isolated a cDNA encoding GRFbeta, a novel 178-amino acid protein whose N terminus is identical to that of GRF1, a calcium-dependent guanine nucleotide exchange factor, and whose C terminus is unrelated to known proteins [16].
  • We found that in rat aortic smooth muscle cells, angiotensin II stimulated the formation of Ras-GTP, Ras-Raf-1 complex formation, and the tyrosine phosphorylation of two important Ras GTPase-activating proteins (GAPs), p120 Ras-GAP and p190 Rho-GAP [17].
  • Furthermore, we found that Ras was capable of binding pyrophosphate (PPi) with a dissociation constant of 26 microM and that PPi and GMP, but neither alone, synergistically potentiated the GRF1-stimulated GDP dissociation from Ras [18].

Regulatory relationships of GRLF1

  • In turn, integrin aggregation by surface tTG inhibits Src kinase activity and decreases activation of the Src substrate p190RhoGAP [19].

Other interactions of GRLF1

  • Like the p190-B exon, the first exon of p190-A is extremely large (3.7 kb in length), encoding both the GTPase and middle domains (residues 1-1228), but not the remaining GAP domain, suggesting a high conservation of genomic structure between two p190 genes [2].
  • Rat p190-A of 1513 amino acids shares 50% sequence identity with human p190-B of 1499 amino acids [2].
  • (2) Full-length p50RhoGAP and p190RhoGAP react less intensely with nonprenylated Rac1 than with the prenylated protein, whereas no difference was observed in the reaction of isolated GAP domains of either p50RhoGAP or Bcr with the different types of Rac1 [20].
  • Phosphorylated Tyr31/118 was found to bind to two src homology (SH)2 domains of p120RasGAP, with coprecipitation of endogenous paxillin with p120RasGAP. p190RhoGAP is known to be a major intracellular binding partner for the p120RasGAP SH2 domains [8].
  • Additionally, early integrin signaling induces activation and tyrosine phosphorylation of p190RhoGAP via a mechanism that requires c-Src [21].

Analytical, diagnostic and therapeutic context of GRLF1

  • Confocal immunofluorescence microscopy revealed that both endogenous and exogenous p190 localized to the newly forming and contracting cleavage furrow of dividing cells [15].
  • Using a combination of partial purification of DNA-binding proteins, DNA-protein interaction by gel shift analysis and preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis, we have identified a protein factor (GRF-1) of 95 kDa which interacts with the human GR gene fragment implicated in homologous down-regulation [22].
  • Electrical stimulation of the rest of the raphe nuclei had no effect on hGRF-induced GH secretion [23].
  • A homologous radioimmunoassay (RIA) system for human growth hormone-releasing factor 1-29NH2 (hGRF 1-29-NH2) was developed and applied to the measurement of immunoreactive (IR) concentrations of the peptide in anaesthetized rats to determine some of its pharmaco-kinetics after i.v. and s.c. administration [24].
  • Intermittent intravenous injection of hGRF, at 3-hour intervals, resulted in a decrease in the magnitude of GH response in normal subjects [25].


  1. Inactivation of Rho GTPases by p190 RhoGAP reduces human pancreatic cancer cell invasion and metastasis. Kusama, T., Mukai, M., Endo, H., Ishikawa, O., Tatsuta, M., Nakamura, H., Inoue, M. Cancer Sci. (2006) [Pubmed]
  2. p190-A, a human tumor suppressor gene, maps to the chromosomal region 19q13.3 that is reportedly deleted in some gliomas. Tikoo, A., Czekay, S., Viars, C., White, S., Heath, J.K., Arden, K., Maruta, H. Gene (2000) [Pubmed]
  3. p190RhoGAP can act to inhibit PDGF-induced gliomas in mice: a putative tumor suppressor encoded on human chromosome 19q13.3. Wolf, R.M., Draghi, N., Liang, X., Dai, C., Uhrbom, L., Eklöf, C., Westermark, B., Holland, E.C., Resh, M.D. Genes Dev. (2003) [Pubmed]
  4. p120-Catenin and p190RhoGAP Regulate Cell-Cell Adhesion by Coordinating Antagonism between Rac and Rho. Wildenberg, G.A., Dohn, M.R., Carnahan, R.H., Davis, M.A., Lobdell, N.A., Settleman, J., Reynolds, A.B. Cell (2006) [Pubmed]
  5. c-Src tyrosine phosphorylation of epidermal growth factor receptor, P190 RhoGAP, and focal adhesion kinase regulates diverse cellular processes. Haskell, M.D., Slack, J.K., Parsons, J.T., Parsons, S.J. Chem. Rev. (2001) [Pubmed]
  6. Suppression of RhoA activity by focal adhesion kinase-induced activation of p190RhoGAP: role in regulation of endothelial permeability. Holinstat, M., Knezevic, N., Broman, M., Samarel, A.M., Malik, A.B., Mehta, D. J. Biol. Chem. (2006) [Pubmed]
  7. Molecular cloning and characterization of a factor that binds the human glucocorticoid receptor gene and represses its expression. LeClerc, S., Palaniswami, R., Xie, B.X., Govindan, M.V. J. Biol. Chem. (1991) [Pubmed]
  8. Localized suppression of RhoA activity by Tyr31/118-phosphorylated paxillin in cell adhesion and migration. Tsubouchi, A., Sakakura, J., Yagi, R., Mazaki, Y., Schaefer, E., Yano, H., Sabe, H. J. Cell Biol. (2002) [Pubmed]
  9. Alpha4beta1 integrin/ligand interaction inhibits alpha5beta1-induced stress fibers and focal adhesions via down-regulation of RhoA and induces melanoma cell migration. Moyano, J.V., Maqueda, A., Casanova, B., Garcia-Pardo, A. Mol. Biol. Cell (2003) [Pubmed]
  10. Role of p190RhoGAP in beta 2 integrin regulation of RhoA in human neutrophils. Dib, K., Melander, F., Andersson, T. J. Immunol. (2001) [Pubmed]
  11. Integrin Signaling through Arg Activates p190RhoGAP by Promoting Its Binding to p120RasGAP and Recruitment to the Membrane. Bradley, W.D., Hern??ndez, S.E., Settleman, J., Koleske, A.J. Mol. Biol. Cell (2006) [Pubmed]
  12. Transforming growth factor beta regulates the expression of the M2 muscarinic receptor in atrial myocytes via an effect on RhoA and p190RhoGAP. Park, H.J., Ward, S.M., Desgrosellier, J.S., Georgescu, S.P., Papageorge, A.G., Zhuang, X., Barnett, J.V., Galper, J.B. J. Biol. Chem. (2006) [Pubmed]
  13. Endostatin associates with lipid rafts and induces reorganization of the actin cytoskeleton via down-regulation of RhoA activity. Wickström, S.A., Alitalo, K., Keski-Oja, J. J. Biol. Chem. (2003) [Pubmed]
  14. RhoA is required for cortical retraction and rigidity during mitotic cell rounding. Maddox, A.S., Burridge, K. J. Cell Biol. (2003) [Pubmed]
  15. p190RhoGAP is cell cycle regulated and affects cytokinesis. Su, L., Agati, J.M., Parsons, S.J. J. Cell Biol. (2003) [Pubmed]
  16. GRFbeta, a novel regulator of calcium signaling, is expressed in pancreatic beta cells and brain. Arava, Y., Seger, R., Walker, M.D. J. Biol. Chem. (1999) [Pubmed]
  17. Angiotensin II controls p21ras activity via pp60c-src. Schieffer, B., Paxton, W.G., Chai, Q., Marrero, M.B., Bernstein, K.E. J. Biol. Chem. (1996) [Pubmed]
  18. Mechanism of the guanine nucleotide exchange reaction of Ras GTPase--evidence for a GTP/GDP displacement model. Zhang, B., Zhang, Y., Shacter, E., Zheng, Y. Biochemistry (2005) [Pubmed]
  19. Cell surface transglutaminase promotes RhoA activation via integrin clustering and suppression of the Src-p190RhoGAP signaling pathway. Janiak, A., Zemskov, E.A., Belkin, A.M. Mol. Biol. Cell (2006) [Pubmed]
  20. Role of prenylation in the interaction of Rho-family small GTPases with GTPase activating proteins. Molnár, G., Dagher, M.C., Geiszt, M., Settleman, J., Ligeti, E. Biochemistry (2001) [Pubmed]
  21. Integrin engagement suppresses RhoA activity via a c-Src-dependent mechanism. Arthur, W.T., Petch, L.A., Burridge, K. Curr. Biol. (2000) [Pubmed]
  22. Purification of a human glucocorticoid receptor gene promoter-binding protein. Production of polyclonal antibodies against the purified factor. Leclerc, S., Xie, B.X., Roy, R., Govindan, M.V. J. Biol. Chem. (1991) [Pubmed]
  23. Suppression of human growth hormone (GH)-releasing hormone-induced GH secretion in pentobarbital-anesthetized rats after electrical stimulation of the midbrain central gray and several raphe nuclei. Koibuchi, N., Kato, M., Kakegawa, T., Suzuki, M. Endocrinology (1988) [Pubmed]
  24. Growth hormone-releasing factor analogue (hGRF1-29NH2): immunoreactive-GRF plasma levels after intravenous and subcutaneous administration. Rafferty, B., Poole, S., Clarke, R., Schulster, D. J. Endocrinol. (1985) [Pubmed]
  25. Investigation of human growth hormone releasing factor in adults. Sassolas, G., Biot-Laporte, S., Cohen, R., Chatelain, P., Boissel, J.P., Dupin, P., Garry, P., Claustrat, B., Girard, P., Borson, F. Horm. Res. (1986) [Pubmed]
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