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ARHGEF2 (rho/rac guanine nucleotide exchange factor (GEF) 2)

Identity

Other namesDKFZp547L106
DKFZp547P1516
GEF
GEF-H1
GEFH1
KIAA0651
LFP40
P40
HGNC (Hugo) ARHGEF2
Location 1q22
Location_base_pair Starts at 154183269 and ends at 154214575 bp from pter ( according to hg18-Mar_2006)  [Mapping]

DNA/RNA

Note Cloning of human ARHGEF2/GEF-H1 from HELA cells. Cloning and characterization of murine (Lfc) and canine (cGEF-H1) rho/rac guanine nucleotide exchange factors homologues to ARHGEF2/GEF-H1.
Transcription 4093 bp mRNA; 2877 bp open reading frame

Protein

 
  A schematics representing the domain structure of full length ARHGEF2/GEF-H1
Description The gene encodes a guanine nucleotide exchange factor for Rho GTPase; 985 amino acids; NH2- Protein kinase C conserved region 1 (zinc finger motif), Dbl-homologous domain (DH domain), pleckstrin homology (PH) domain - coiled coil c-terminus domain -COOH.
Expression Wide (cochlea, bone marrow, lymph, blood, lung, ovary, cranial nerve, lymph node, colon, spleen, kidney, muscle, eye, bone, cervix, nerve, adrenal gland, heart, skin, thyroid, uterus, testis, pancreas, brain, mouth, stomach, thymus, pharynx, prostate, vascular, mammary gland, placenta).
Localisation Microtubules
Function ARHGEF2/GEF-H1 belongs to a Dbl family of Rho activators and exhibits Rho-specific GDP/GTP exchange activity for RhoA but not for Rac1 or Cdc42. ARHGEF2/GEF-H1 activity is downregulated by interaction of its C-terminus with microtubules. Therefore, ARHGEF2/GEF-H1 links changes in microtubule integrity to Rho-dependent regulation of the actin cytoskeleton. Activated RhoA transduces various signals into downstream signaling cascades, such as cytoskeleton reorganization, cellular invasion, and cell proliferation, all of which contribute to cancer progression.
Like other RhoGEF Dbl members, ARHGEF2/GEF-H1 possesses the Dbl-homology (DH) domain responsible for its GEF activity the pleckstrin-homology (PH) domain, adjacent and C-terminal to the DH domain. In addition, ARHGEF2/GEF-H1 also contains a cysteine-rich zinc finger-like motif at its amino terminus and a proline-rich coiled coil domain at its carboxy terminus. The N- and C-terminal motifs mediate microtubule localization of ARHGEF2/GEF-H1. Point mutated (cys53 to arg) in a zinc finger-like motif, as well as N- and C-terminally truncated ARHGEF2/GEF-H1 proteins are loosing ability to bind microtubules. These truncated forms have no affect on microtubule stability, and displaying even higher GEF activity then microtubule-bound forms. The coiled coil domain at C-terminus may interact with SH3 domain-containing proteins and has a potential binding site for 14-3-3 proteins. The ser885 within the 14-3-3-binding site is a phosphorylation site for p21-activated kinase 1 (PAK1), an effector of RAC and CDC42 GTPases. The phosphorylation of ARHGEF2/GEFH1 by PAK may coordinate Rac/Cdc42- and Rho-dependent signaling pathways.
Homology The high level of homology has been shown for three known rho/rac guanine nucleotide exchange factors originated from human, mouse and dog.

Implicated in

Entity gastrointestinal mesenchymal malignancies
Disease Microarray analysis identified ARHGEF2/GEF-H1 as one of response markers for a treatment of gastrointestinal stromal tumors, implicating its role in the development of gastrointestinal mesenchymal malignancies.
Oncogenesis A cell line transformed by ARHGEF2/GEF-H1 transfection can induce tumor development after injection into nude mice. The increased ARHGEF2/GEF-H1 expression was found contributing to the tumor progression phenotype associated with the p53 mutation.
  

External links

Nomenclature
HGNC (Hugo)ARHGEF2   682
Entrez_Gene (NCBI)ARHGEF2  9181  Rho/Rac guanine nucleotide exchange factor (GEF) 2
Cards
AtlasARHGEF2ID43150ch1q22
GeneCards (Weizmann)ARHGEF2
Ensembl (Hinxton)ENSG00000116584 [Gene_View]  ARHGEF2 [Vega]
AceView (NCBI)ARHGEF2
Genatlas (Paris)ARHGEF2
euGene (Indiana)9181
SOURCE (Stanford)NM_001162383 NM_001162384 NM_004723
Gene Expression (Array Express) ENSG00000116584
Genomic and cartography
GoldenPath (UCSC)ARHGEF2  -  1q22   chr1:154183269-154214575 -  1q21-q22   [Description]    (hg18-Mar_2006)
EnsemblARHGEF2 - 1q21-q22 [CytoView]
Mapping of homologs : NCBIARHGEF2 [Mapview]
OMIM607560   
Gene and transcription
Gene : Genbank (Entrez)AB014551 AF486838 AI925929 AK127366 AK295924
Reference sequence (RefSeq transcript) :SRSNM_001162383 NM_001162384 NM_004723
Reference transcript : EntrezNM_001162383 NM_001162384 NM_004723
RefSeq genomic : SRSAC_000044 AC_000133 NC_000001 NT_004487 NW_001838531 NW_925683
RefSeq genomic : EntrezAC_000044 AC_000133 NC_000001 NT_004487 NW_001838531 NW_925683
Consensus coding sequences : CCDS NCBIARHGEF2
Cluster EST : UnigeneHs.516790 [ SRS ] Hs.516790 [ NCBI ]
Alternative Splicing : Fast-db (Paris)17384
Protein : pattern, domain, 3D structure
Protein : UniProt/SwissProtQ92974 (SRS) Q92974 (Expasy) Q92974 (Uniprot)
With graphics : InterProQ92974
Splice isoforms : VarSplice FASTAQ92974(VarSplice FASTA)
Domaine pattern : Prosite (SRS)DH_1 (PS00741)    DH_2 (PS50010)    PH_DOMAIN (PS50003)    ZF_DAG_PE_1 (PS00479)    ZF_DAG_PE_2 (PS50081)   
Domain pattern : Prosite (Expaxy)DH_1 (PS00741)    DH_2 (PS50010)    PH_DOMAIN (PS50003)    ZF_DAG_PE_1 (PS00479)    ZF_DAG_PE_2 (PS50081)   
Domains : Interpro (SRS)DH-domain    PH_type    Pleckstrin_homology    Prot_Kinase_C-like_PE/DAG_bd   
Domains : Interpro (EBI)DH-domain    PH_type    Pleckstrin_homology    Prot_Kinase_C-like_PE/DAG_bd   
Related proteins : CluSTrQ92974
Domain families : Pfam SRSPH (PF00169)    RhoGEF (PF00621)   
Domain families : Pfam SangerPH (PF00169)    RhoGEF (PF00621)   
Domain families : Pfam NCBIpfam00169    pfam00621   
Domain families : Smart EMBLC1 (SM00109)  PH (SM00233)  RhoGEF (SM00325)  
Blocks (Seattle)Q92974
Crystal structure of protein : PDB SRS
Crystal structure of protein : PDBSum
Crystal structure of protein : IMB
Crystal structure of protein : PDB RSDB
HPRD10458
Protein Interaction databases
DIP (DOE-UCLA)Q92974
IntAct (EBI)Q92974
Polymorphism : SNP, mutations, diseases
Single Nucleotide Polymorphism (SNP) : dbSNP NCBIARHGEF2
SNP : GeneSNP UtahARHGEF2
SNP : HGBaseARHGEF2
Genetic variants : HAPMAPARHGEF2
Somatic Mutations in Cancer : COSMICARHGEF2 
Mutations and Diseases : HGMDARHGEF2
Hereditary diseases : OMIM607560   
Hereditary diseases : GENETests607560   
Diseases : Genetic AssociationARHGEF2
General knowledge
Homologs : HomoloGeneARHGEF2
Homology/Alignments : Family Browser UCSCARHGEF2
Phylogenetic Trees/Animal Genes : TreeFamARHGEF2
Chemical/Protein Interactions : CTD9181
Keywords Ontology : AmiGOcell morphogenesis  guanyl-nucleotide exchange factor activity  intracellular  cytoplasm  Golgi apparatus  spindle  cytosol  cytoskeleton  microtubule  tight junction  intracellular protein transport  apoptosis  actin filament organization  negative regulation of microtubule depolymerization  cell cycle  mitosis  intracellular signaling cascade  microtubule binding  zinc ion binding  induction of apoptosis by extracellular signals  cell junction  Rac guanyl-nucleotide exchange factor activity  regulation of Rho protein signal transduction  regulation of cell proliferation  metal ion binding  Rac GTPase binding  cell division  
Keywords Ontology : EGO-EBIcell morphogenesis  guanyl-nucleotide exchange factor activity  intracellular  cytoplasm  Golgi apparatus  spindle  cytosol  cytoskeleton  microtubule  tight junction  intracellular protein transport  apoptosis  actin filament organization  negative regulation of microtubule depolymerization  cell cycle  mitosis  intracellular signaling cascade  microtubule binding  zinc ion binding  induction of apoptosis by extracellular signals  cell junction  Rac guanyl-nucleotide exchange factor activity  regulation of Rho protein signal transduction  regulation of cell proliferation  metal ion binding  Rac GTPase binding  cell division  
Pathways : BIOCARTA
Pathways : KEGG
Other databases
Probes
Probes : ImagenesARHGEF2 Related clones (RZPD - Berlin)
Literature
PubMed34 Pubmed reference(s) in Entrez
PubGeneARHGEF2

Bibliography

Cloning and characterization of GEF-H1, a microtubule-associated guanine nucleotide exchange factor for Rac and Rho GTPases.
Ren Y, Li R, Zheng Y, Busch H
The Journal of biological chemistry. 1998 ; 273 (52) : 34954-34960.
PMID 9857026
 
The Dbl-related protein, Lfc, localizes to microtubules and mediates the activation of Rac signaling pathways in cells.
Glaven JA, Whitehead I, Bagrodia S, Kay R, Cerione RA
The Journal of biological chemistry. 1999 ; 274 (4) : 2279-2285.
PMID 9890991
 
Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton.
Krendel M, Zenke FT, Bokoch GM
Nature cell biology. 2002 ; 4 (4) : 294-301.
PMID 11912491
 
Identification of a tight junction-associated guanine nucleotide exchange factor that activates Rho and regulates paracellular permeability.
Benais-Pont G, Punn A, Flores-Maldonado C, Eckert J, Raposo G, Fleming TP, Cereijido M, Balda MS, Matter K
The Journal of cell biology. 2003 ; 160 (5) : 729-740.
PMID 12604587
 
p21-activated kinase 1 phosphorylates and regulates 14-3-3 binding to GEF-H1, a microtubule-localized Rho exchange factor.
Zenke FT, Krendel M, DerMardirossian C, King CC, Bohl BP, Bokoch GM
The Journal of biological chemistry. 2004 ; 279 (18) : 18392-18400.
PMID 14970201
 
Activation of gef-h1, a guanine nucleotide exchange factor for RhoA, by DNA transfection.
Brecht M, Steenvoorden AC, Collard JG, Luf S, Erz D, Bartram CR, Janssen JW
International journal of cancer. Journal international du cancer. 2005 ; 113 (4) : 533-540.
PMID 15455375
 
Mutant p53 induces the GEF-H1 oncogene, a guanine nucleotide exchange factor-H1 for RhoA, resulting in accelerated cell proliferation in tumor cells.
Mizuarai S, Yamanaka K, Kotani H
Cancer research. 2006 ; 66 (12) : 6319-6326.
PMID 16778209
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written05-2007Valery Poroyko, Anna Birukova
The University of Chicago, Department of Medicine, Section of Pulmonary and Critical Care, 929 E. 57th Street, GCIS Bldg, Office W410, Chicago, IL 60637. USA

Citation

This paper should be referenced as such :
Poroyko V, Birukova A . ARHGEF2 (rho/rac guanine nucleotide exchange factor (GEF) 2). Atlas Genet Cytogenet Oncol Haematol. May 2007 .
URL : http://AtlasGeneticsOncology.org/Genes/ARHGEF2ID43150ch1q22.html

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indexed on : Sat Feb 27 10:54:13 CET 2010

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