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Gene Review

ARHGAP1  -  Rho GTPase activating protein 1

Homo sapiens

Synonyms: CDC42 GTPase-activating protein, CDC42GAP, Cdc42GAP, GTPase-activating protein rhoOGAP, RHOGAP, ...
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Disease relevance of ARHGAP1


Psychiatry related information on ARHGAP1


High impact information on ARHGAP1


Chemical compound and disease context of ARHGAP1


Biological context of ARHGAP1


Anatomical context of ARHGAP1

  • NIH3T3 cells overexpressing RhoGAP showed considerable inhibition of stress fiber formation [4].
  • The RhoGAP transcript is truncated in some breast carcinoma cell lines and it has low expression in other breast cancer cell lines as compared to a normal breast cell line [4].
  • Podosome-like structures present at the leading edge in wild-type neutrophils were significantly reduced in CDC42GAP(-/-) cells [16].
  • Similar morphological changes were observed in HtTA-1 HeLa cells expressing just the myr 5 Rho-GAP domain but not in cells expressing myr 5 M1695 [17].
  • These results suggest that p200RhoGAP is involved in the regulation of neurite outgrowth by exerting its RhoGAP activity and that its cellular activity may be regulated through interaction with Src-like tyrosine kinases [18].

Associations of ARHGAP1 with chemical compounds

  • This argues that the introduction of the arginine finger is insufficient for GAP activity and that the GAP must fulfill an additional function, one possibility being the engagement and stabilization of the conformationally sensitive switch regions of Cdc42 [14].
  • ExoS Rho GTPase-activating protein activity stimulates reorganization of the actin cytoskeleton through Rho GTPase guanine nucleotide disassociation inhibitor [2].
  • The results suggest that GEF facilitates nucleotide exchange by destabilizing both bound nucleotide and Mg(2+), whereas RhoGAP utilizes the Mg(2+) cofactor to achieve high catalytic efficiency and specificity [19].
  • Using glutathione S-transferase recombinant proteins, immunoprecipitation studies, and yeast two-hybrid assays, it was found that BNIP-2 and Cdc42GAP could form homo and hetero complexes via their conserved BCH domains [20].
  • It consists of an N-terminal RhoGAP domain and a C-terminal proline-rich region [21].

Physical interactions of ARHGAP1

  • Cells expressing the BNIP-2 mutants devoid of this motif or/and the 34-amino acids immediately upstream to this sequence failed to elicit cell elongation and membrane protrusions despite that the protein still remained in the cytoplasm and interacted with Cdc42GAP [22].
  • These results provide the first evidence that a RhoGAP functionally interacts with cortactin and represents a novel determinant in the regulation of cell dynamics [23].
  • In addition, we have replaced the conserved arginine (Arg305), which was suggested by structural studies to be a key catalytic residue, with an alanine and found that the R305A Cdc42-GAP mutant has a greatly diminished catalytic capacity but is still able to bind Cdc42 with high affinity [24].

Regulatory relationships of ARHGAP1

  • The complex of a heterotrimeric G protein with its activating protein shows that the latter protein does not participate directly in the hydrolytic reaction and has a different structure of RhoGAP and RasGAP [25].
  • Tyrosine phosphorylation of p250GAP by Fyn would regulate its RhoGAP activity, subcellular localization, or interactions with other proteins, leading to morphological and phenotypic changes of oligodendrocytes [26].
  • Furthermore, we found that GTP hydrolysis by TC10 in the vicinity of the plasma membrane was dependent on Rac and the redox-regulated Rho GAP, p190RhoGAP-A [27].
  • Aurora B kinase is known to regulate localization of centralspindlin and may regulate the activity of the RhoGAP component of centralspindlin [28].
  • Taken together, these results suggest that ET-1 induces Rho-kinase activation and subsequent phosphorylation of p190A RhoGAP, leading to prolonged RhoA activation [29].

Other interactions of ARHGAP1

  • Thus, CDC42GAP may function as a link between CDC42 and other signaling pathways [30].
  • Deletion experiments indicated that the BCH domain of BNIPL-2 is critical for its interactions with the Bcl-2 and Cdc42GAP and also for its cell death-inducing function [1].
  • ARHGAP27 and ARHGAP12 shared the common-domain structure, consisting of SH3, WW, PH, and RhoGAP domains [31].
  • Our findings provide evidence that cell morphology changes and migration are coordinated via multiple domains in BPGAP1 and present a novel mode of regulation for cell dynamics by a RhoGAP protein [32].
  • However, the 85 kDa regulatory subunit (p85) of the phosphoinositide 3-kinase (PI-3K) is homologous with the Cdc42GAP and contains the essential arginine residue, but is ineffective as a GAP [14].

Analytical, diagnostic and therapeutic context of ARHGAP1


  1. BNIPL-2, a novel homologue of BNIP-2, interacts with Bcl-2 and Cdc42GAP in apoptosis. Qin, W., Hu, J., Guo, M., Xu, J., Li, J., Yao, G., Zhou, X., Jiang, H., Zhang, P., Shen, L., Wan, D., Gu, J. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  2. ExoS Rho GTPase-activating protein activity stimulates reorganization of the actin cytoskeleton through Rho GTPase guanine nucleotide disassociation inhibitor. Sun, J., Barbieri, J.T. J. Biol. Chem. (2004) [Pubmed]
  3. ARHGAP8 is a novel member of the RHOGAP family related to ARHGAP1/CDC42GAP/p50RHOGAP: mutation and expression analyses in colorectal and breast cancers. Johnstone, C.N., Castellví-Bel, S., Chang, L.M., Bessa, X., Nakagawa, H., Harada, H., Sung, R.K., Piqué, J.M., Castells, A., Rustgi, A.K. Gene (2004) [Pubmed]
  4. Chromosome 13q12 encoded Rho GTPase activating protein suppresses growth of breast carcinoma cells, and yeast two-hybrid screen shows its interaction with several proteins. Nagaraja, G.M., Kandpal, R.P. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  5. Rho GTPase-activating protein deleted in liver cancer suppresses cell proliferation and invasion in hepatocellular carcinoma. Wong, C.M., Yam, J.W., Ching, Y.P., Yau, T.O., Leung, T.H., Jin, D.Y., Ng, I.O. Cancer Res. (2005) [Pubmed]
  6. Deletion including the oligophrenin-1 gene associated with enlarged cerebral ventricles, cerebellar hypoplasia, seizures and ataxia. Tentler, D., Gustavsson, P., Leisti, J., Schueler, M., Chelly, J., Timonen, E., Annerén, G., Willard, H.F., Dahl, N. Eur. J. Hum. Genet. (1999) [Pubmed]
  7. Induction of RhoGAP and pathological changes characteristic of Alzheimer's disease by UAHFEMF discharge in rat brain. Chang, I.F., Hsiao, H.Y. Current Alzheimer research. (2005) [Pubmed]
  8. Structure at 1.65 A of RhoA and its GTPase-activating protein in complex with a transition-state analogue. Rittinger, K., Walker, P.A., Eccleston, J.F., Smerdon, S.J., Gamblin, S.J. Nature (1997) [Pubmed]
  9. ARAP1: a point of convergence for Arf and Rho signaling. Miura, K., Jacques, K.M., Stauffer, S., Kubosaki, A., Zhu, K., Hirsch, D.S., Resau, J., Zheng, Y., Randazzo, P.A. Mol. Cell (2002) [Pubmed]
  10. The crystal structure of rna1p: a new fold for a GTPase-activating protein. Hillig, R.C., Renault, L., Vetter, I.R., Drell, T., Wittinghofer, A., Becker, J. Mol. Cell (1999) [Pubmed]
  11. Golgi-localized GAP for Cdc42 functions downstream of ARF1 to control Arp2/3 complex and F-actin dynamics. Dubois, T., Paléotti, O., Mironov, A.A., Fraisier, V., Stradal, T.E., De Matteis, M.A., Franco, M., Chavrier, P. Nat. Cell Biol. (2005) [Pubmed]
  12. Two novel types of contiguous gene deletion of the AVPR2 and ARHGAP4 genes in unrelated Japanese kindreds with nephrogenic diabetes insipidus. Demura, M., Takeda, Y., Yoneda, T., Furukawa, K., Usukura, M., Itoh, Y., Mabuchi, H. Hum. Mutat. (2002) [Pubmed]
  13. Tyrosine phosphorylation of the Bcl-2-associated protein BNIP-2 by fibroblast growth factor receptor-1 prevents its binding to Cdc42GAP and Cdc42. Low, B.C., Lim, Y.P., Lim, J., Wong, E.S., Guy, G.R. J. Biol. Chem. (1999) [Pubmed]
  14. Understanding the catalytic mechanism of GTPase-activating proteins: demonstration of the importance of switch domain stabilization in the stimulation of GTP hydrolysis. Fidyk, N.J., Cerione, R.A. Biochemistry (2002) [Pubmed]
  15. Regulation of RhoA GTP hydrolysis by the GTPase-activating proteins p190, p50RhoGAP, Bcr, and 3BP-1. Zhang, B., Zheng, Y. Biochemistry (1998) [Pubmed]
  16. Rho GTPase CDC42 regulates directionality and random movement via distinct MAPK pathways in neutrophils. Szczur, K., Xu, H., Atkinson, S., Zheng, Y., Filippi, M.D. Blood (2006) [Pubmed]
  17. The rat myosin myr 5 is a GTPase-activating protein for Rho in vivo: essential role of arginine 1695. Müller, R.T., Honnert, U., Reinhard, J., Bähler, M. Mol. Biol. Cell (1997) [Pubmed]
  18. Characterization of a brain-specific Rho GTPase-activating protein, p200RhoGAP. Moon, S.Y., Zang, H., Zheng, Y. J. Biol. Chem. (2003) [Pubmed]
  19. The role of Mg2+ cofactor in the guanine nucleotide exchange and GTP hydrolysis reactions of Rho family GTP-binding proteins. Zhang, B., Zhang, Y., Wang, Z., Zheng, Y. J. Biol. Chem. (2000) [Pubmed]
  20. The BNIP-2 and Cdc42GAP homology domain of BNIP-2 mediates its homophilic association and heterophilic interaction with Cdc42GAP. Low, B.C., Seow, K.T., Guy, G.R. J. Biol. Chem. (2000) [Pubmed]
  21. The human orthologue of CdGAP is a phosphoprotein and a GTPase-activating protein for Cdc42 and Rac1 but not RhoA. Tcherkezian, J., Triki, I., Stenne, R., Danek, E.I., Lamarche-Vane, N. Biol. Cell (2006) [Pubmed]
  22. BNIP-2 induces cell elongation and membrane protrusions by interacting with Cdc42 via a unique Cdc42-binding motif within its BNIP-2 and Cdc42GAP homology domain. Zhou, Y.T., Guy, G.R., Low, B.C. Exp. Cell Res. (2005) [Pubmed]
  23. BPGAP1 interacts with cortactin and facilitates its translocation to cell periphery for enhanced cell migration. Lua, B.L., Low, B.C. Mol. Biol. Cell (2004) [Pubmed]
  24. Biochemical studies of the mechanism of action of the Cdc42-GTPase-activating protein. Leonard, D.A., Lin, R., Cerione, R.A., Manor, D. J. Biol. Chem. (1998) [Pubmed]
  25. GTPase-activating proteins and their complexes. Gamblin, S.J., Smerdon, S.J. Curr. Opin. Struct. Biol. (1998) [Pubmed]
  26. p250GAP, a neural RhoGAP protein, is associated with and phosphorylated by Fyn. Taniguchi, S., Liu, H., Nakazawa, T., Yokoyama, K., Tezuka, T., Yamamoto, T. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  27. GTP hydrolysis by the Rho family GTPase TC10 promotes exocytic vesicle fusion. Kawase, K., Nakamura, T., Takaya, A., Aoki, K., Namikawa, K., Kiyama, H., Inagaki, S., Takemoto, H., Saltiel, A.R., Matsuda, M. Dev. Cell (2006) [Pubmed]
  28. Cytokinesis: a logical GAP. Mishima, M., Glotzer, M. Curr. Biol. (2003) [Pubmed]
  29. Rho-kinase contributes to sustained RhoA activation through phosphorylation of p190A RhoGAP. Mori, K., Amano, M., Takefuji, M., Kato, K., Morita, Y., Nishioka, T., Matsuura, Y., Murohara, T., Kaibuchi, K. J. Biol. Chem. (2009) [Pubmed]
  30. Cloning and expression of a human CDC42 GTPase-activating protein reveals a functional SH3-binding domain. Barfod, E.T., Zheng, Y., Kuang, W.J., Hart, M.J., Evans, T., Cerione, R.A., Ashkenazi, A. J. Biol. Chem. (1993) [Pubmed]
  31. Identification and characterization of ARHGAP27 gene in silico. Katoh, Y., Katoh, M. Int. J. Mol. Med. (2004) [Pubmed]
  32. Concerted regulation of cell dynamics by BNIP-2 and Cdc42GAP homology/Sec14p-like, proline-rich, and GTPase-activating protein domains of a novel Rho GTPase-activating protein, BPGAP1. Shang, X., Zhou, Y.T., Low, B.C. J. Biol. Chem. (2003) [Pubmed]
  33. 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]
  34. A putative Xenopus Rho-GTPase activating protein (XrGAP) gene is expressed in the notochord and brain during the early embryogenesis. Kim, J., Shim, S., Choi, S.C., Han, J.K. Gene Expr. Patterns (2003) [Pubmed]
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