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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

Other aliasDKFZp547L106
DKFZp547P1516
GEF
GEF-H1
GEFH1
KIAA0651
LFP40
P40
LocusID (NCBI) 9181
Atlas_Id 43150
Location 1q22  [Link to chromosome band 1q22]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
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


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(1;13)(q22;q12) PSPC1/ARHGEF2


External links

Nomenclature
Cards
AtlasARHGEF2ID43150ch1q22.txt
Aliases
Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)9181
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
Miscellaneous
canSAR (ICR) (select the gene name)
Probes
Litterature
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed


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indexed on : Thu Oct 18 17:28:32 CEST 2018

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