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| | A schematics representing the domain structure of full length ARHGEF2/GEF-H1 |
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| 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. |
| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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