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ARHGAP4  -  Rho GTPase activating protein 4

Homo sapiens

Synonyms: C1, KIAA0131, RGC1, RHOGAP4, Rho GTPase-activating protein 4, ...
 
 
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Disease relevance of ARHGAP4

  • Two novel types of contiguous gene deletion of the AVPR2 and ARHGAP4 genes in unrelated Japanese kindreds with nephrogenic diabetes insipidus [1].
  • Patients with hereditary angioedema lack C-1 inhibitor, a plasma alpha 2-glycoprotein that inhibits both the proteolytic action of C1, the activated first component of the complement system, and the activity of components of the contact phase of coagulation: kallikrein, factor XIa, and factor XIIa [2].
  • Cells transformed by simian sarcoma virus (SSV) express a 115000-dalton protein ( p115 ) that is precipitated by a goat antiserum to disrupted SSV/SSAV-infected and transformed cells but not by antibodies directed against the viral gag protein, p30, or envelope proteins [3].
  • C1-inhibitor biosynthesis by Hep G2 hepatoma cells was assessed by enzyme-linked immunosorbant assay, by metabolic labeling followed by immunoprecipitation, and by Northern blotting [4].
  • With the use of Epstein-Barr virus (EBV)-infected B cells as a model for CBF1 mediated CD23a expression, C1 was found to be EBV inducible [5].
 

Psychiatry related information on ARHGAP4

  • In C3 the reaction time (RT) had to be faster than the shortest mean RT from C1 and C2 in order to stop the aversive stimulus [6].
  • Complement C1-inhibitor expression in Alzheimer's disease [7].
 

High impact information on ARHGAP4

  • The maize C1 gene, which also encodes a Myb homolog, activates both the A1 and Bz1 genes, but only in the presence of a basic-helix-loop-helix coactivator encoded by the maize genes R or B [8].
  • Such patients have been shown to have low levels of C4 and C2, the natural substrates for C-1, but the levels were not correlated with the presence of symptoms [2].
  • Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis [9].
  • Hedgehog ligands are post-translationally modified by cholesterol, and the Hedgehog receptor, Patched, is structurally similar to the Niemann-Pick C1 protein, which functions in intracellular lipid transport [10].
  • Fusion constructs between the wild-type C1 cDNA and the dominant inhibitor allele C1-I cDNA were used to identify the amino acid changes in C1 responsible for the C1-I inhibitory phenotype [11].
 

Chemical compound and disease context of ARHGAP4

  • Compound deletion of the rhoGAP C1 and V2 vasopressin receptor genes in a patient with nephrogenic diabetes insipidus [12].
  • We have compared the relative abilities of these inhibitors to reduce the toxicity of in vitro exposures to tubercidin against clonogenic progenitor cells of normal human bone marrow (CFU-GEMM, BFU-E, CFU-GM) and of two leukemic human cell lines (HL-60/C1, CCRF-CEM) that differ in their expression of transporter subtypes [13].
  • The feasibility of imaging pentose cycle (PC) glucose utilization in human gliomas with PET was explored in two rat glioma models by means of glucose radiolabeled in either the carbon-1 (C-1) or carbon-6 (C-6) position [14].
  • RESULTS: In vitro, the C-1/C-6 ratio for CO2 production from T-36B-10 monolayers was 8.8 +/- 0.4 (s.d.), in glioma slices it was 6.1 +/- 2.1 and in normal brain slices it was 1.1 +/- 0 [14].
  • A new gene, qscR, encoding a LysR-type transcriptional regulator that is a homolog of CbbR, has been characterized from the facultative methylotroph Methylobacterium extorquens AM1 and shown to be the major regulator of the serine cycle, the specific C1 assimilation pathway [15].
 

Biological context of ARHGAP4

  • Subcellularly, endogenous ARHGAP4 expression localized to the Golgi complex and could redistribute to the microtubules, for example during mitosis [16].
  • Among the genes recently identified at the tip of the long arm of the human X chromosome, a novel gene, C1, encodes a protein that appears to represent a newly discovered member of the group of signaling proteins involved in regulation of the small GTP binding proteins of the ras superfamily [17].
  • The putative DNA-binding region of C1 fused to the transcriptional activation domain of GAL4 activated transcription of anthocyanin structural gene promoters in c1 aleurones, c1 Rscm2 embryos, and c1 r embryogenic callus [11].
  • The light chain of both these enzymes provided the binding site for C1 inactivator [18].
  • Phosphorylation inhibits binding to p115, a vesicle-tethering protein, and has been implicated as an important step in the mitotic Golgi fragmentation process [19].
 

Anatomical context of ARHGAP4

 

Associations of ARHGAP4 with chemical compounds

  • Here, we present the cloning of rat ARHGAP4, a member of the Rho GTPase activating protein family, and also demonstrate its close linkage to the vasopressin 2 receptor gene [16].
  • Analysis of the abnormal inhibitors by sodium dodecyl sulfate (SDS) acrylamide gel electrophoresis suggested that each consisted of a single polypeptide chain, the mobility of which was slower than that of the normal C1 inactivator [23].
  • In contrast, neither reduction of giantin below detectable levels, nor inhibition of p115 binding to GM130, had any detectable effect on Golgi structure or Golgi reassembly after cell division or brefeldin A washout [24].
  • We show that P is required for accumulation in the pericarp of transcripts of two genes (A1 and C2) encoding enzymes for flavonoid biosynthesis--genes also regulated by C1 in the aleurone [25].
  • This is indicated by the unresponsiveness of the RNA-stimulated hyperphosphorylation to casein kinase II inhibitors, and the distinct glycerol gradient sedimentation profiles of the basal versus RNA-stimulated C1 hnRNP protein phosphorylation activities from nuclear extracts [26].
 

Other interactions of ARHGAP4

  • Other patients with NDI, but without immunodeficiency, have had deletions that remove all ARHGAP4 except exon 1; however, no other patients have had deletions of the highly conserved intragenic region between ARHGAP4 and ARD1A [27].
  • Using part of the MEKK1 N-terminus in a yeast two-hybrid screen, we discovered a novel interaction with p115 Rho GTPase-activating protein (GAP) [28].
  • The protein encoded by C1, p115, is synthesized predominantly in cells of hematopoietic origin [17].
  • The C1 gene at Xq28 encodes a protein assumed to function as a Rho GTPase-activating protein (rhoGAP) [12].
 

Analytical, diagnostic and therapeutic context of ARHGAP4

  • We discuss the dominant phenotype of C1-I with respect to its possible repressor function in contrast to the activator function of the C1 gene product [29].
  • By electrophoretic mobility shift assays, we identified a transcription factor complex (C1) that binds sequence specific to one known and 4 newly identified putative CBF1 recognition sites in the CD23a core promoter region [5].
  • PATIENTS AND METHODS: Twenty-nine patients were randomized to receive either regimen G or C first (G1 and C1, respectively) and underwent two leukaphereses [30].
  • Quantitation of secreted recombinant C1 inhibitor by radioimmunoassay indicated that 72 h after transfection the level was approximately 2.2 micrograms/ml [31].
  • Affinity chromatography of serum on Sepharose-IgG resulted in the binding of C1; subsequent washing with EDTA removed only C1s and C1t [32].

References

  1. 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]
  2. Prekallikrein activation and high-molecular-weight kininogen consumption in hereditary angioedema. Schapira, M., Silver, L.D., Scott, C.F., Schmaier, A.H., Prograis, L.J., Curd, J.G., Colman, R.W. N. Engl. J. Med. (1983) [Pubmed]
  3. Virus-specific phosphoproteins in simian sarcoma virus-transformed primate cells. Born, M., von der Helm, K., Deinhardt, F. EMBO J. (1982) [Pubmed]
  4. C1-inhibitor-serine proteinase complexes and the biosynthesis of C1-inhibitor by Hep G2 and U 937 cells. Patston, P.A., Medcalf, R.L., Kourteva, Y., Schapira, M. Blood (1993) [Pubmed]
  5. Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia. Hubmann, R., Schwarzmeier, J.D., Shehata, M., Hilgarth, M., Duechler, M., Dettke, M., Berger, R. Blood (2002) [Pubmed]
  6. Controllability of an aversive stimulus in depressed patients and health controls: a study using slow brain potentials. Bolz, J., Giedke, H. Biol. Psychiatry (1981) [Pubmed]
  7. Complement C1-inhibitor expression in Alzheimer's disease. Veerhuis, R., Janssen, I., Hoozemans, J.J., De Groot, C.J., Hack, C.E., Eikelenboom, P. Acta Neuropathol. (1998) [Pubmed]
  8. The myb-homologous P gene controls phlobaphene pigmentation in maize floral organs by directly activating a flavonoid biosynthetic gene subset. Grotewold, E., Drummond, B.J., Bowen, B., Peterson, T. Cell (1994) [Pubmed]
  9. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Carstea, E.D., Morris, J.A., Coleman, K.G., Loftus, S.K., Zhang, D., Cummings, C., Gu, J., Rosenfeld, M.A., Pavan, W.J., Krizman, D.B., Nagle, J., Polymeropoulos, M.H., Sturley, S.L., Ioannou, Y.A., Higgins, M.E., Comly, M., Cooney, A., Brown, A., Kaneski, C.R., Blanchette-Mackie, E.J., Dwyer, N.K., Neufeld, E.B., Chang, T.Y., Liscum, L., Strauss, J.F., Ohno, K., Zeigler, M., Carmi, R., Sokol, J., Markie, D., O'Neill, R.R., van Diggelen, O.P., Elleder, M., Patterson, M.C., Brady, R.O., Vanier, M.T., Pentchev, P.G., Tagle, D.A. Science (1997) [Pubmed]
  10. Cholesterol in signal transduction. Incardona, J.P., Eaton, S. Curr. Opin. Cell Biol. (2000) [Pubmed]
  11. Identification of functional domains in the maize transcriptional activator C1: comparison of wild-type and dominant inhibitor proteins. Goff, S.A., Cone, K.C., Fromm, M.E. Genes Dev. (1991) [Pubmed]
  12. Compound deletion of the rhoGAP C1 and V2 vasopressin receptor genes in a patient with nephrogenic diabetes insipidus. Schöneberg, T., Pasel, K., von Baehr, V., Schulz, A., Volk, H.D., Gudermann, T., Filler, G. Hum. Mutat. (1999) [Pubmed]
  13. A comparison of the abilities of nitrobenzylthioinosine, dilazep, and dipyridamole to protect human hematopoietic cells from 7-deazaadenosine (tubercidin). Cass, C.E., King, K.M., Montaño, J.T., Janowska-Wieczorek, A. Cancer Res. (1992) [Pubmed]
  14. Feasibility of imaging pentose cycle glucose metabolism in gliomas with PET: studies in rat brain tumor models. Spence, A.M., Graham, M.M., Muzi, M., Freeman, S.D., Link, J.M., Grierson, J.R., O'Sullivan, F., Stein, D., Abbott, G.L., Krohn, K.A. J. Nucl. Med. (1997) [Pubmed]
  15. QscR, a LysR-type transcriptional regulator and CbbR homolog, is involved in regulation of the serine cycle genes in Methylobacterium extorquens AM1. Kalyuzhnaya, M.G., Lidstrom, M.E. J. Bacteriol. (2003) [Pubmed]
  16. Cloning of rat ARHGAP4/C1, a RhoGAP family member expressed in the nervous system that colocalizes with the Golgi complex and microtubules. Foletta, V.C., Brown, F.D., Young, W.S. Brain Res. Mol. Brain Res. (2002) [Pubmed]
  17. An X chromosome-linked gene encoding a protein with characteristics of a rhoGAP predominantly expressed in hematopoietic cells. Tribioli, C., Droetto, S., Bione, S., Cesareni, G., Torrisi, M.R., Lotti, L.V., Lanfrancone, L., Toniolo, D., Pelicci, P. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  18. Studies on human plasma C1 inactivator-enzyme interactions. I. Mechanisms of interaction with C1s, plasmin, and trypsin. Harpel, P.C., Cooper, N.R. J. Clin. Invest. (1975) [Pubmed]
  19. The mitotic phosphorylation cycle of the cis-Golgi matrix protein GM130. Lowe, M., Gonatas, N.K., Warren, G. J. Cell Biol. (2000) [Pubmed]
  20. Rac-1 regulates nuclear factor of activated T cells (NFAT) C1 nuclear translocation in response to Fcepsilon receptor type 1 stimulation of mast cells. Turner, H., Gomez, M., McKenzie, E., Kirchem, A., Lennard, A., Cantrell, D.A. J. Exp. Med. (1998) [Pubmed]
  21. Synthesis of C1 inhibitor in fibroblasts from patients with type I and type II hereditary angioneurotic edema. Kramer, J., Katz, Y., Rosen, F.S., Davis, A.E., Strunk, R.C. J. Clin. Invest. (1991) [Pubmed]
  22. Crucial residues in the carboxy-terminal end of C1 inhibitor revealed by pathogenic mutants impaired in secretion or function. Verpy, E., Couture-Tosi, E., Eldering, E., Lopez-Trascasa, M., Späth, P., Meo, T., Tosi, M. J. Clin. Invest. (1995) [Pubmed]
  23. Studies on human plasma C1 inactivator-enzyme interactions. II. Structural features of an abnormal C1 inactivator from a kindred with hereditary angioneurotic edema. Harpel, P.C., Hugli, T.E., Cooper, N.R. J. Clin. Invest. (1975) [Pubmed]
  24. Evidence that Golgi structure depends on a p115 activity that is independent of the vesicle tether components giantin and GM130. Puthenveedu, M.A., Linstedt, A.D. J. Cell Biol. (2001) [Pubmed]
  25. Alternatively spliced products of the maize P gene encode proteins with homology to the DNA-binding domain of myb-like transcription factors. Grotewold, E., Athma, P., Peterson, T. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  26. RNA-dependent phosphorylation of a nuclear RNA binding protein. Fung, P.A., Labrecque, R., Pederson, T. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  27. Severe combined immunodeficiency associated with nephrogenic diabetes insipidus and a deletion in the Xq28 region. Broides, A., Ault, B.H., Arthus, M.F., Bichet, D.G., Conley, M.E. Clin. Immunol. (2006) [Pubmed]
  28. p115 Rho GTPase activating protein interacts with MEKK1. Christerson, L.B., Gallagher, E., Vanderbilt, C.A., Whitehurst, A.W., Wells, C., Kazempour, R., Sternweis, P.C., Cobb, M.H. J. Cell. Physiol. (2002) [Pubmed]
  29. Molecular analysis of the C1-I allele from Zea mays: a dominant mutant of the regulatory C1 locus. Paz-Ares, J., Ghosal, D., Saedler, H. EMBO J. (1990) [Pubmed]
  30. Randomized cross-over trial of progenitor-cell mobilization: high-dose cyclophosphamide plus granulocyte colony-stimulating factor (G-CSF) versus granulocyte-macrophage colony-stimulating factor plus G-CSF. Koç, O.N., Gerson, S.L., Cooper, B.W., Laughlin, M., Meyerson, H., Kutteh, L., Fox, R.M., Szekely, E.M., Tainer, N., Lazarus, H.M. J. Clin. Oncol. (2000) [Pubmed]
  31. Expression of functional human C1 inhibitor in COS cells. Eldering, E., Nuijens, J.H., Hack, C.E. J. Biol. Chem. (1988) [Pubmed]
  32. The macromolecular structure of the first component of complement. Assimeh, S.N., Painter, R.H. J. Immunol. (1975) [Pubmed]
 
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