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

Written2007-05Valery Poroyko, Anna Birukova
The University of Chicago, Department of Medicine, Section of Pulmonary, Critical Care, 929 E. 57th Street, GCIS Bldg, Office W410, Chicago, IL 60637. USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesrho/rac guanine nucleotide exchange factor (GEF) 2
Rho/Rac guanine nucleotide exchange factor (GEF) 2
Alias_symbol (synonym)LFP40
GEF-H1
KIAA0651
P40
HGNC (Hugo) ARHGEF2
LocusID (NCBI) 9181
Atlas_Id 43150
Location 1q22  [Link to chromosome band 1q22]
Location_base_pair Starts at 155916630 and ends at 155948336 bp from pter ( according to hg19-Feb_2009)  [Mapping ARHGEF2.png]
Fusion genes
(updated 2016)
ARHGEF2 (1q22) / RAB6A (11q13.4)ARHGEF2 (1q22) / SMG5 (1q22)ARHGEF2 (1q22) / SSR2 (1q22)
ASH1L (1q22) / ARHGEF2 (1q22)PSPC1 (13q12.11) / ARHGEF2 (1q22)

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

Note
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.
  

Bibliography

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
 
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
 
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
 
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
 
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
 
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
 

Citation

This paper should be referenced as such :
Poroyko, Valery ; Birukova, Anna
ARHGEF2 (rho/rac guanine nucleotide exchange factor (GEF) 2)
Atlas Genet Cytogenet Oncol Haematol. 2007;11(4):292-293.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/ARHGEF2ID43150ch1q22.html


External links

Nomenclature
HGNC (Hugo)ARHGEF2   682
Cards
AtlasARHGEF2ID43150ch1q22
Entrez_Gene (NCBI)ARHGEF2  9181  Rho/Rac guanine nucleotide exchange factor 2
AliasesGEF; GEF-H1; GEFH1; LFP40; 
P40
GeneCards (Weizmann)ARHGEF2
Ensembl hg19 (Hinxton)ENSG00000116584 [Gene_View]  chr1:155916630-155948336 [Contig_View]  ARHGEF2 [Vega]
Ensembl hg38 (Hinxton)ENSG00000116584 [Gene_View]  chr1:155916630-155948336 [Contig_View]  ARHGEF2 [Vega]
ICGC DataPortalENSG00000116584
TCGA cBioPortalARHGEF2
AceView (NCBI)ARHGEF2
Genatlas (Paris)ARHGEF2
WikiGenes9181
SOURCE (Princeton)ARHGEF2
Genetics Home Reference (NIH)ARHGEF2
Genomic and cartography
GoldenPath hg19 (UCSC)ARHGEF2  -     chr1:155916630-155948336 -  1q21-q22   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)ARHGEF2  -     1q21-q22   [Description]    (hg38-Dec_2013)
EnsemblARHGEF2 - 1q21-q22 [CytoView hg19]  ARHGEF2 - 1q21-q22 [CytoView hg38]
Mapping of homologs : NCBIARHGEF2 [Mapview hg19]  ARHGEF2 [Mapview hg38]
OMIM607560   
Gene and transcription
Genbank (Entrez)AB014551 AF486838 AI925929 AK127366 AK295924
RefSeq transcript (Entrez)NM_001162383 NM_001162384 NM_004723
RefSeq genomic (Entrez)NC_000001 NC_018912 NT_004487 NW_004929293
Consensus coding sequences : CCDS (NCBI)ARHGEF2
Cluster EST : UnigeneHs.743352 [ NCBI ]
CGAP (NCI)Hs.743352
Alternative Splicing GalleryENSG00000116584
Gene ExpressionARHGEF2 [ NCBI-GEO ]   ARHGEF2 [ EBI - ARRAY_EXPRESS ]   ARHGEF2 [ SEEK ]   ARHGEF2 [ MEM ]
Gene Expression Viewer (FireBrowse)ARHGEF2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9181
GTEX Portal (Tissue expression)ARHGEF2
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ92974   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ92974  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ92974
Splice isoforms : SwissVarQ92974
PhosPhoSitePlusQ92974
Domaine pattern : Prosite (Expaxy)DH_2 (PS50010)    PH_DOMAIN (PS50003)    ZF_DAG_PE_1 (PS00479)    ZF_DAG_PE_2 (PS50081)   
Domains : Interpro (EBI)DH-domain    PE/DAG-bd    PH_dom-like    PH_domain   
Domain families : Pfam (Sanger)PH_13 (PF16652)    RhoGEF (PF00621)   
Domain families : Pfam (NCBI)pfam16652    pfam00621   
Domain families : Smart (EMBL)C1 (SM00109)  PH (SM00233)  RhoGEF (SM00325)  
Conserved Domain (NCBI)ARHGEF2
DMDM Disease mutations9181
Blocks (Seattle)ARHGEF2
SuperfamilyQ92974
Human Protein AtlasENSG00000116584
Peptide AtlasQ92974
HPRD10458
IPIIPI00291316   IPI00472160   IPI00940816   IPI00908313   IPI00643259   IPI01010245   
Protein Interaction databases
DIP (DOE-UCLA)Q92974
IntAct (EBI)Q92974
FunCoupENSG00000116584
BioGRIDARHGEF2
STRING (EMBL)ARHGEF2
ZODIACARHGEF2
Ontologies - Pathways
QuickGOQ92974
Ontology : AmiGOestablishment of mitotic spindle orientation  cell morphogenesis  guanyl-nucleotide exchange factor activity  Rho guanyl-nucleotide exchange factor activity  Rho guanyl-nucleotide exchange factor activity  protein binding  cytoplasm  Golgi apparatus  spindle  cytosol  cytoskeleton  microtubule  bicellular tight junction  focal adhesion  intracellular protein transport  actin filament organization  negative regulation of microtubule depolymerization  mitotic nuclear division  microtubule binding  transcription factor binding  zinc ion binding  cytoplasmic, membrane-bounded vesicle  Rho GTPase binding  Rac guanyl-nucleotide exchange factor activity  vesicle  ruffle membrane  positive regulation of interleukin-6 production  positive regulation of tumor necrosis factor production  regulation of Rho protein signal transduction  intracellular signal transduction  regulation of cell proliferation  neuronal cell body  positive regulation of apoptotic process  dendritic shaft  protein complex  positive regulation of GTPase activity  positive regulation of GTPase activity  positive regulation of GTPase activity  innate immune response  positive regulation of transcription from RNA polymerase II promoter  Rac GTPase binding  positive regulation of peptidyl-tyrosine phosphorylation  negative regulation of neurogenesis  regulation of small GTPase mediated signal transduction  positive regulation of NF-kappaB transcription factor activity  cell division  negative regulation of necroptotic process  cellular response to muramyl dipeptide  cellular response to tumor necrosis factor  cellular hyperosmotic response  neuronal postsynaptic density  negative regulation of extrinsic apoptotic signaling pathway via death domain receptors  negative regulation of intrinsic apoptotic signaling pathway in response to osmotic stress  
Ontology : EGO-EBIestablishment of mitotic spindle orientation  cell morphogenesis  guanyl-nucleotide exchange factor activity  Rho guanyl-nucleotide exchange factor activity  Rho guanyl-nucleotide exchange factor activity  protein binding  cytoplasm  Golgi apparatus  spindle  cytosol  cytoskeleton  microtubule  bicellular tight junction  focal adhesion  intracellular protein transport  actin filament organization  negative regulation of microtubule depolymerization  mitotic nuclear division  microtubule binding  transcription factor binding  zinc ion binding  cytoplasmic, membrane-bounded vesicle  Rho GTPase binding  Rac guanyl-nucleotide exchange factor activity  vesicle  ruffle membrane  positive regulation of interleukin-6 production  positive regulation of tumor necrosis factor production  regulation of Rho protein signal transduction  intracellular signal transduction  regulation of cell proliferation  neuronal cell body  positive regulation of apoptotic process  dendritic shaft  protein complex  positive regulation of GTPase activity  positive regulation of GTPase activity  positive regulation of GTPase activity  innate immune response  positive regulation of transcription from RNA polymerase II promoter  Rac GTPase binding  positive regulation of peptidyl-tyrosine phosphorylation  negative regulation of neurogenesis  regulation of small GTPase mediated signal transduction  positive regulation of NF-kappaB transcription factor activity  cell division  negative regulation of necroptotic process  cellular response to muramyl dipeptide  cellular response to tumor necrosis factor  cellular hyperosmotic response  neuronal postsynaptic density  negative regulation of extrinsic apoptotic signaling pathway via death domain receptors  negative regulation of intrinsic apoptotic signaling pathway in response to osmotic stress  
Pathways : BIOCARTAPhosphoinositides and their downstream targets. [Genes]   
Pathways : KEGGPathogenic Escherichia coli infection   
REACTOMEQ92974 [protein]
REACTOME PathwaysR-HSA-194840 Rho GTPase cycle [pathway]
REACTOME PathwaysR-HSA-193648 NRAGE signals death through JNK [pathway]
REACTOME PathwaysR-HSA-416482 G alpha (12/13) signalling events [pathway]
NDEx NetworkARHGEF2
Atlas of Cancer Signalling NetworkARHGEF2
Wikipedia pathwaysARHGEF2
Orthology - Evolution
OrthoDB9181
GeneTree (enSembl)ENSG00000116584
Phylogenetic Trees/Animal Genes : TreeFamARHGEF2
HOVERGENQ92974
HOGENOMQ92974
Homologs : HomoloGeneARHGEF2
Homology/Alignments : Family Browser (UCSC)ARHGEF2
Gene fusions - Rearrangements
Fusion : MitelmanPSPC1/ARHGEF2 [13q12.11/1q22]  [t(1;13)(q22;q12)]  
Fusion: TCGAARHGEF2 1q22 SMG5 1q22 HNSC
Fusion: TCGAARHGEF2 1q22 SSR2 1q22 BRCA
Fusion: TCGAASH1L 1q22 ARHGEF2 1q22 BRCA
Fusion: TCGAPSPC1 13q12.11 ARHGEF2 1q22 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerARHGEF2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ARHGEF2
dbVarARHGEF2
ClinVarARHGEF2
1000_GenomesARHGEF2 
Exome Variant ServerARHGEF2
ExAC (Exome Aggregation Consortium)ARHGEF2 (select the gene name)
Genetic variants : HAPMAP9181
Genomic Variants (DGV)ARHGEF2 [DGVbeta]
DECIPHER (Syndromes)1:155916630-155948336  ENSG00000116584
CONAN: Copy Number AnalysisARHGEF2 
Mutations
ICGC Data PortalARHGEF2 
TCGA Data PortalARHGEF2 
Broad Tumor PortalARHGEF2
OASIS PortalARHGEF2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICARHGEF2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDARHGEF2
intOGen PortalARHGEF2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch ARHGEF2
DgiDB (Drug Gene Interaction Database)ARHGEF2
DoCM (Curated mutations)ARHGEF2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)ARHGEF2 (select a term)
intoGenARHGEF2
NCG5 (London)ARHGEF2
Cancer3DARHGEF2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM607560   
Orphanet
MedgenARHGEF2
Genetic Testing Registry ARHGEF2
NextProtQ92974 [Medical]
TSGene9181
GENETestsARHGEF2
Huge Navigator ARHGEF2 [HugePedia]
snp3D : Map Gene to Disease9181
BioCentury BCIQARHGEF2
ClinGenARHGEF2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD9181
Chemical/Pharm GKB GenePA24972
Clinical trialARHGEF2
Miscellaneous
canSAR (ICR)ARHGEF2 (select the gene name)
Probes
Litterature
PubMed85 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineARHGEF2
EVEXARHGEF2
GoPubMedARHGEF2
iHOPARHGEF2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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