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

• Cloning of rat ARHGAP4/C1, a RhoGAP family member expressed in the nervous system that colocalizes with the Golgi complex and microtubules [16].
• Its localization in a narrow cytoplasmic region just below the plasma membrane and its inhibitory effect on stress fiber organization indicate that p115 may down regulate rho-like GTPases in hematopoietic cells [17].
• Rac-1 regulates nuclear factor of activated T cells (NFAT) C1 nuclear translocation in response to Fcepsilon receptor type 1 stimulation of mast cells [20].
• Synthesis of C1 inhibitor in fibroblasts from patients with type I and type II hereditary angioneurotic edema [21].
• Presence of low levels of both dysfunctional proteins in patient plasmas defies the conventional classification of C1 inhibitor deficiencies as type I or type II [22].

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