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Gene Review

ARHGEF7  -  Rho guanine nucleotide exchange factor...

Homo sapiens

Synonyms: BETA-PIX, Beta-Pix, COOL-1, COOL1, DKFZp686C12170, ...
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Disease relevance of ARHGEF7

  • Genomic structure of the human beta-PIX gene and its alteration in gastric cancer [1].
  • In this study, we demonstrated that Nef from HIV-1 binds to the regulatory subunit (p85) of phosphatidylinositol-3-kinase (PI3K) [2].
  • Family members from four generations were found to have polycythemia and increased whole blood O2 affinity (P50; 11 mm Hg; normal, 27 mm Hg) [3].
  • Oxygen transport to and substrate turnover in leg muscle were studied at rest and during light and heavy upright bicycle exercise in two brothers with a hereditary hemoglobinopathy associated with high oxygen affinity (P50 = 13 mmHg) [4].
  • Oxygen delivery and consumption and P50 in patients with acute myocardial infarction [5].

Psychiatry related information on ARHGEF7

  • Similar mechanisms are thus likely to underlie the mental retardation induced by mutations of ARHGEF6 and PAK3 [6].
  • Although schizotypal subjects have been shown to have deficits in sensorimotor gating as measured by prepulse inhibition, to the authors' knowledge P50 sensory gating in schizotypal personality disorder has yet to be reported [7].
  • RESULTS: Alzheimer's disease patients showed less P50 suppression following the second click relative to the comparison subjects [8].
  • P50 suppression in bipolar disorder patients without a history of psychosis did not differ from that of the healthy subjects [9].
  • Sensory gating in chronic posttraumatic stress disorder: reduced auditory P50 suppression in combat veterans [10].

High impact information on ARHGEF7

  • The three-dimensional structure of the SH3 domain in the p85 subunit of the phosphatidylinositol 3-kinase (PI3K) has been determined by multidimensional NMR methods [11].
  • Twenty-two smokers with elevated hematocrits (mean, 54 per cent) had elevated blood carboxyhemoglobin (mean, 11.6 per cent; normal, less than 1 per cent) and a "left-shifted" oxygen-hemoglobin dissociation curve (mean P50, 21.6 +/- 2.3 [+/- S.D.] torr; normal, 26.7 +/- 1.1) [12].
  • Thus, rapamycin inhibits a signal transduction element that is necessary for the activation of p70 S6 kinase and mitogenesis but unnecessary for activation of p85 Rsk S6 kinase or MAP kinase [13].
  • Neohemocytes are substantially smaller than erythrocytes, contain 15.1 grams per decaliter of hemoglobin, and have a P50 value (the partial pressure of oxygen at which the hemoglobin is half-saturated) of 24.0 torr [14].
  • These opposing chemistries result in a maximal nitrite reduction rate when Hb is 40-60% saturated with oxygen (near the Hb P50), an apparent ideal set point for hypoxia-responsive NO generation [15].

Chemical compound and disease context of ARHGEF7


Biological context of ARHGEF7

  • To directly address this issue, transfection studies with wild-type and mutant p85 betaPIX (S525A/T526A, a non-phosphorylatable form) were performed [21].
  • The beta-PIX gene has 17 exons and an A/T polymorphism at the 32nd base upstream of the intron/exon junction of exon 7 [1].
  • In addition, we examined the gene-expression profile in another set of 30 gastric samples, but no significant over-expression of either the beta-PIX gene or the alpha-PIX gene was found [1].
  • A PI3K activity-independent function of p85 regulatory subunit in control of mammalian cytokinesis [22].
  • A mutant form of p85 betaPIX (S525A/T526A), in which the major phosphorylation sites are replaced by alanine, shows significant defect in targeting [23].

Anatomical context of ARHGEF7


Associations of ARHGEF7 with chemical compounds

  • One pathway involves the coupling of the src-related tyrosine kinase Lyn to the "classical" p85/p110 form of phosphatidylinositol 3-kinase [27].
  • The severe oxidative limitation was characterized by impaired muscle oxygen extraction indicated by subnormal systemic arteriovenous oxygen difference (a-v O2 diff) in maximal exercise (patient = 4.0 ml/dl, normal men = 16.7 +/- 2.1) despite normal oxygen carrying capacity and Hgb-O2 P50 [28].
  • The high 2,3-diphosphoglycerate level caused a shift to the right of the oxygen dissociation curve (P50 = 32.9 mm Hg) [29].
  • Mutation of Y-785 to phenylalanine somewhat impaired receptor phosphorylation activity, which was reflected in reduced GAP and p85 phosphorylation [30].
  • Biochemical and RNA-interference studies demonstrated that HPIP influences ERalpha-dependent rapid estrogen signaling by acting as a scaffold protein and recruits Src kinase and the p85 subunit of phosphatidylinositol 3-kinase to a complex with ERalpha, which in turn stimulates AKT and MAPK [31].

Regulatory relationships of ARHGEF7


Other interactions of ARHGEF7


Analytical, diagnostic and therapeutic context of ARHGEF7

  • Surface plasmon resonance and molecular modeling identified the phosphorylated-Y(71) residue of a p85-binding pYXXM motif in the first sst2 intracellular loop, and p85 COOH-terminal SH2 as direct interacting domains [36].
  • Pure recombinant hemoglobin S was shown to be identical to natural sickle hemoglobin in its ultraviolet and visible absorption bands and by gel electrophoresis, isoelectric focusing, amino acid analysis, mass spectrometry, partial N-terminal sequencing, and functional properties (P50, cooperativity, and response to 2,3-bisphosphoglycerate) [37].
  • The microinjection results were confirmed through the use of an affinity-purified antibody directed against p85, which gave the same phenotype [38].
  • Immunofluorescence studies performed on cells transfected with p85 or lyt-10C alpha expression vectors showed that both the abnormal proteins were constitutively localized in the nucleus [39].
  • Immunoprecipitation analysis of UV-cross-linked DNA-protein adducts showed that p85 can bind kappa B sites in its unprocessed form [39].


  1. Genomic structure of the human beta-PIX gene and its alteration in gastric cancer. Li, Z., Wang, Y., Song, J., Kataoka, H., Yoshii, S., Gao, C., Wang, Y., Zhou, J., Ota, S., Tanaka, M., Sugimura, H. Cancer Lett. (2002) [Pubmed]
  2. Interaction between Nef and phosphatidylinositol-3-kinase leads to activation of p21-activated kinase and increased production of HIV. Linnemann, T., Zheng, Y.H., Mandic, R., Peterlin, B.M. Virology (2002) [Pubmed]
  3. Hemoglobin Syracuse (alpha2beta2-143(H21)His leads to Pro), a new high-affinity variant detected by special electrophoretic methods. Observations on the auto-oxidation of normal and variant hemoglobins. Jensen, M., Oski, F.A., Nathan, D.G., Bunn, H.F. J. Clin. Invest. (1975) [Pubmed]
  4. Tissue oxygenation and muscular substrate turnover in two subjects with high hemoglobin oxygen affinity. Wranne, B., Berlin, G., Jorfeldt, L., Lund, N. J. Clin. Invest. (1983) [Pubmed]
  5. Oxygen delivery and consumption and P50 in patients with acute myocardial infarction. Yang, S.C., Puri, V.K., Raheja, R. Circulation (1986) [Pubmed]
  6. Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis. Nod??-Langlois, R., Muller, D., Boda, B. J. Cell. Sci. (2006) [Pubmed]
  7. Sensory gating deficits assessed by the P50 event-related potential in subjects with schizotypal personality disorder. Cadenhead, K.S., Light, G.A., Geyer, M.A., Braff, D.L. The American journal of psychiatry. (2000) [Pubmed]
  8. Sensory gating deficit expressed by a disturbed suppression of the P50 event-related potential in patients with Alzheimer's disease. Jessen, F., Kucharski, C., Fries, T., Papassotiropoulos, A., Hoenig, K., Maier, W., Heun, R. The American journal of psychiatry. (2001) [Pubmed]
  9. Diminished suppression of the P50 auditory evoked potential in bipolar disorder subjects with a history of psychosis. Olincy, A., Martin, L. The American journal of psychiatry. (2005) [Pubmed]
  10. Sensory gating in chronic posttraumatic stress disorder: reduced auditory P50 suppression in combat veterans. Neylan, T.C., Fletcher, D.J., Lenoci, M., McCallin, K., Weiss, D.S., Schoenfeld, F.B., Marmar, C.R., Fein, G. Biol. Psychiatry (1999) [Pubmed]
  11. Structure of the PI3K SH3 domain and analysis of the SH3 family. Koyama, S., Yu, H., Dalgarno, D.C., Shin, T.B., Zydowsky, L.D., Schreiber, S.L. Cell (1993) [Pubmed]
  12. Smokers' polycythemia. Smith, J.R., Landaw, S.A. N. Engl. J. Med. (1978) [Pubmed]
  13. Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Price, D.J., Grove, J.R., Calvo, V., Avruch, J., Bierer, B.E. Science (1992) [Pubmed]
  14. Synthesis and evaluation of a prototypal artificial red cell. Hunt, C.A., Burnette, R.R., MacGregor, R.D., Strubbe, A.E., Lau, D.T., Taylor, N., Kiwada, H. Science (1985) [Pubmed]
  15. Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control. Huang, Z., Shiva, S., Kim-Shapiro, D.B., Patel, R.P., Ringwood, L.A., Irby, C.E., Huang, K.T., Ho, C., Hogg, N., Schechter, A.N., Gladwin, M.T. J. Clin. Invest. (2005) [Pubmed]
  16. Effects of methylprednisolone on P50, 2,3 diphosphoglycerate and arteriovenous oxygen difference in acute myocardial infarction. Kalter, E.S., Henning, R.J., Thijs, L., Vincent, J.L., Becker, H., Carlson, R.W., Weil, M.H. Circulation (1980) [Pubmed]
  17. Erythrocyte O2 transport and metabolism and effects of vitamin B6 therapy in type II diabetes mellitus. Solomon, L.R., Cohen, K. Diabetes (1989) [Pubmed]
  18. Cocaine abusers have reduced auditory P50 amplitude and suppression compared to both normal controls and alcoholics. Fein, G., Biggins, C., MacKay, S. Biol. Psychiatry (1996) [Pubmed]
  19. Activation of Epstein-Barr virus/C3d receptor (gp140, CR2, CD21) on human B lymphoma cell surface triggers Cbl tyrosine phosphorylation, its association with p85 subunit, Crk-L and Syk and its dissociation with Vav. Lottin-Divoux, S., Jean, D., Le Romancer, M., Frade, R. Cell. Signal. (2006) [Pubmed]
  20. Tropisetron improves deficits in auditory P50 suppression in schizophrenia. Koike, K., Hashimoto, K., Takai, N., Shimizu, E., Komatsu, N., Watanabe, H., Nakazato, M., Okamura, N., Stevens, K.E., Freedman, R., Iyo, M. Schizophr. Res. (2005) [Pubmed]
  21. Basic fibroblast growth factor stimulates activation of Rac1 through a p85 betaPIX phosphorylation-dependent pathway. Shin, E.Y., Woo, K.N., Lee, C.S., Koo, S.H., Kim, Y.G., Kim, W.J., Bae, C.D., Chang, S.I., Kim, E.G. J. Biol. Chem. (2004) [Pubmed]
  22. A PI3K activity-independent function of p85 regulatory subunit in control of mammalian cytokinesis. Garc??a, Z., Silio, V., Marqu??s, M., Cort??s, I., Kumar, A., Hernandez, C., Checa, A.I., Serrano, A., Carrera, A.C. EMBO J. (2006) [Pubmed]
  23. Phosphorylation of p85 beta PIX, a Rac/Cdc42-specific guanine nucleotide exchange factor, via the Ras/ERK/PAK2 pathway is required for basic fibroblast growth factor-induced neurite outgrowth. Shin, E.Y., Shin, K.S., Lee, C.S., Woo, K.N., Quan, S.H., Soung, N.K., Kim, Y.G., Cha, C.I., Kim, S.R., Park, D., Bokoch, G.M., Kim, E.G. J. Biol. Chem. (2002) [Pubmed]
  24. GIT2 represses Crk- and Rac1-regulated cell spreading and Cdc42-mediated focal adhesion turnover. Frank, S.R., Adelstein, M.R., Hansen, S.H. EMBO J. (2006) [Pubmed]
  25. Regulation of phosphatidylinositol 3-kinase activity and phosphatidylinositol 3,4,5-trisphosphate accumulation by neutrophil priming agents. Cadwallader, K.A., Condliffe, A.M., McGregor, A., Walker, T.R., White, J.F., Stephens, L.R., Chilvers, E.R. J. Immunol. (2002) [Pubmed]
  26. Human SPA-1 gene product selectively expressed in lymphoid tissues is a specific GTPase-activating protein for Rap1 and Rap2. Segregate expression profiles from a rap1GAP gene product. Kurachi, H., Wada, Y., Tsukamoto, N., Maeda, M., Kubota, H., Hattori, M., Iwai, K., Minato, N. J. Biol. Chem. (1997) [Pubmed]
  27. A tyrosine kinase signaling pathway accounts for the majority of phosphatidylinositol 3,4,5-trisphosphate formation in chemoattractant-stimulated human neutrophils. Ptasznik, A., Prossnitz, E.R., Yoshikawa, D., Smrcka, A., Traynor-Kaplan, A.E., Bokoch, G.M. J. Biol. Chem. (1996) [Pubmed]
  28. Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect. Haller, R.G., Henriksson, K.G., Jorfeldt, L., Hultman, E., Wibom, R., Sahlin, K., Areskog, N.H., Gunder, M., Ayyad, K., Blomqvist, C.G. J. Clin. Invest. (1991) [Pubmed]
  29. Erythrocyte metabolism in purine nucleoside phosphorylase deficiency after enzyme replacement therapy by infusion of erythrocytes. Staal, G.E., Stoop, J.W., Zegers, B.J., Siegenbeek van Heukelom, L.H., van der Vlist, M.J., Wadman, S.K., Martin, D.W. J. Clin. Invest. (1980) [Pubmed]
  30. Tyrosine 785 is a major determinant of Trk--substrate interaction. Obermeier, A., Halfter, H., Wiesmüller, K.H., Jung, G., Schlessinger, J., Ullrich, A. EMBO J. (1993) [Pubmed]
  31. An inherent role of microtubule network in the action of nuclear receptor. Manavathi, B., Acconcia, F., Rayala, S.K., Kumar, R. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  32. Cdc42 and PAK-mediated signaling leads to Jun kinase and p38 mitogen-activated protein kinase activation. Bagrodia, S., Dérijard, B., Davis, R.J., Cerione, R.A. J. Biol. Chem. (1995) [Pubmed]
  33. Interaction of alphaPIX (ARHGEF6) with beta-parvin (PARVB) suggests an involvement of alphaPIX in integrin-mediated signaling. Rosenberger, G., Jantke, I., Gal, A., Kutsche, K. Hum. Mol. Genet. (2003) [Pubmed]
  34. Characterization of rhoGAP. A GTPase-activating protein for rho-related small GTPases. Lancaster, C.A., Taylor-Harris, P.M., Self, A.J., Brill, S., van Erp, H.E., Hall, A. J. Biol. Chem. (1994) [Pubmed]
  35. A cascade involving p85, Cdc42 and septin 2 regulates cytokinesis. Silió, V., Marqués, M., Cortés, I., Zuluaga, S., Carrera, A.C. Biochem. Soc. Trans. (2007) [Pubmed]
  36. Direct binding of p85 to sst2 somatostatin receptor reveals a novel mechanism for inhibiting PI3K pathway. Bousquet, C., Guillermet-Guibert, J., Saint-Laurent, N., Archer-Lahlou, E., Lopez, F., Fanjul, M., Ferrand, A., Fourmy, D., Pichereaux, C., Monsarrat, B., Pradayrol, L., Estève, J.P., Susini, C. EMBO J. (2006) [Pubmed]
  37. Recombinant human sickle hemoglobin expressed in yeast. Martin de Llano, J.J., Schneewind, O., Stetler, G., Manning, J.M. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  38. Microinjection of the SH2 domain of the 85-kilodalton subunit of phosphatidylinositol 3-kinase inhibits insulin-induced DNA synthesis and c-fos expression. Jhun, B.H., Rose, D.W., Seely, B.L., Rameh, L., Cantley, L., Saltiel, A.R., Olefsky, J.M. Mol. Cell. Biol. (1994) [Pubmed]
  39. Rearranged NFKB-2 genes in lymphoid neoplasms code for constitutively active nuclear transactivators. Chang, C.C., Zhang, J., Lombardi, L., Neri, A., Dalla-Favera, R. Mol. Cell. Biol. (1995) [Pubmed]
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