ARHGEF1 explained

Rho guanine nucleotide exchange factor 1 is a protein that in humans is encoded by the ARHGEF1 gene.^{[1] [2] [3]} This protein is also called RhoGEF1 or p115-RhoGEF.

Function

Rho guanine nucleotide exchange factor 1 is guanine nucleotide exchange factor (GEF) for the RhoA small GTPase protein.^[4] Rho is a small GTPase protein that is inactive when bound to the guanine nucleotide GDP. But when acted on by Rho GEF proteins such as RhoGEF1, this GDP is released and replaced by GTP, leading to the active state of Rho. In this active, GTP-bound conformation, Rho can bind to and activate specific effector proteins and enzymes to regulate cellular functions.^[5] In particular, active Rho is a major regulator of the cell actin cytoskeleton.^[5]

RhoGEF1 is a member of a group of four RhoGEF proteins known to be activated by G protein coupled receptors coupled to the G₁₂ and G₁₃ heterotrimeric G proteins.^{[6] [7]} The others are ARHGEF11 (also known as PDZ-RhoGEF), ARHGEF12 (also known as LARG) and AKAP13 (also known as ARHGEF13 and Lbc). ^{[8] [9]} GPCR-regulated RhoGEF1 (and these related GEF proteins) acts as an effector for G₁₂ and G₁₃ G proteins. In addition to being activated by G₁₂ or G₁₃ G proteins, three of these four RhoGEF proteins (ARHGEF1/11/12) also function as RGS family GTPase-activating proteins (GAPs) to increase the rate of GTP hydrolysis of G₁₂/G₁₃ alpha proteins (which are themselves GTPase proteins). This action increases the rate of G protein deactivation, limiting the time during which these RhoGEFs activate Rho.^[10]

Multiple alternatively spliced transcript variants have been identified for this gene, but the full-length nature and function of some variants has not been defined.^[3]

Interactions

ARHGEF1 has been shown to interact with:

• CD44^[11]
• GNA12^[11]
• GNA13^[7]
• P110α^[12]

See also

• Second messenger system
• G protein-coupled receptor
• Heterotrimeric G protein
• Small GTPases
• Rho family of GTPases

References

Further reading

• Bhattacharyya R, Wedegaertner PB . Galpha 13 requires palmitoylation for plasma membrane localization, Rho-dependent signaling, and promotion of p115-RhoGEF membrane binding . The Journal of Biological Chemistry . 275 . 20 . 14992–9 . May 2000 . 10747909 . 10.1074/jbc.M000415200 . free .
• Wells CD, Gutowski S, Bollag G, Sternweis PC . Identification of potential mechanisms for regulation of p115 RhoGEF through analysis of endogenous and mutant forms of the exchange factor . The Journal of Biological Chemistry . 276 . 31 . 28897–905 . August 2001 . 11384980 . 10.1074/jbc.M102913200 . free .
• Chen Z, Wells CD, Sternweis PC, Sprang SR . Structure of the rgRGS domain of p115RhoGEF . Nature Structural Biology . 8 . 9 . 805–9 . September 2001 . 11524686 . 10.1038/nsb0901-805 . 11040143 .
• Chen Z, Singer WD, Wells CD, Sprang SR, Sternweis PC . Mapping the Galpha13 binding interface of the rgRGS domain of p115RhoGEF . The Journal of Biological Chemistry . 278 . 11 . 9912–9 . March 2003 . 12525488 . 10.1074/jbc.M212695200 . free .
• Bhattacharyya R, Wedegaertner PB . Characterization of G alpha 13-dependent plasma membrane recruitment of p115RhoGEF . The Biochemical Journal . 371 . Pt 3 . 709–20 . May 2003 . 12534370 . 1223324 . 10.1042/BJ20021897 .
• Bhattacharyya R, Wedegaertner PB . Mutation of an N-terminal acidic-rich region of p115-RhoGEF dissociates alpha13 binding and alpha13-promoted plasma membrane recruitment . FEBS Letters . 540 . 1–3 . 211–6 . April 2003 . 12681510 . 10.1016/S0014-5793(03)00267-9 . 84132104 .
• Bourguignon LY, Singleton PA, Zhu H, Diedrich F . Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine (macrophage-colony stimulating factor) production and breast tumor progression . The Journal of Biological Chemistry . 278 . 32 . 29420–34 . August 2003 . 12748184 . 10.1074/jbc.M301885200 . free .
• Holinstat M, Mehta D, Kozasa T, Minshall RD, Malik AB . Protein kinase Calpha-induced p115RhoGEF phosphorylation signals endothelial cytoskeletal rearrangement . The Journal of Biological Chemistry . 278 . 31 . 28793–8 . August 2003 . 12754211 . 10.1074/jbc.M303900200 . free .

Notes and References

1. Hart MJ, Sharma S, elMasry N, Qiu RG, McCabe P, Polakis P, Bollag G . Identification of a novel guanine nucleotide exchange factor for the Rho GTPase . The Journal of Biological Chemistry . 271 . 41 . 25452–8 . October 1996 . 8810315 . 10.1074/jbc.271.41.25452 . free .
2. Aasheim HC, Pedeutour F, Smeland EB . Characterization, expression and chromosomal localization of a human gene homologous to the mouse Lsc oncogene, with strongest expression in hematopoetic tissues . Oncogene . 14 . 14 . 1747–52 . April 1997 . 9135076 . 10.1038/sj.onc.1200994 . 24528606 .
3. Web site: Entrez Gene: ARHGEF1 Rho guanine nucleotide exchange factor (GEF) 1.
4. Hart MJ, Sharma S, elMasry N, Qiu RG, McCabe P, Polakis P, Bollag G . Identification of a novel guanine nucleotide exchange factor for the Rho GTPase . The Journal of Biological Chemistry . 271 . 41 . 25452–8 . October 1996 . 8810315 . 10.1074/jbc.271.41.25452 . free .
5. Thumkeo D, Watanabe S, Narumiya S . Physiological roles of Rho and Rho effectors in mammals . European Journal of Cell Biology . 92 . 10–11 . 303–15 . Oct–Nov 2013 . 24183240 . 10.1016/j.ejcb.2013.09.002 .
6. Kozasa T, Jiang X, Hart MJ, Sternweis PM, Singer WD, Gilman AG, Bollag G, Sternweis PC . p115 RhoGEF, a GTPase activating protein for Galpha12 and Galpha13 . Science . 280 . 5372 . 2109–11 . June 1998 . 9641915 . 10.1126/science.280.5372.2109 .
7. Hart MJ, Jiang X, Kozasa T, Roscoe W, Singer WD, Gilman AG, Sternweis PC, Bollag G . Direct stimulation of the guanine nucleotide exchange activity of p115 RhoGEF by Galpha13 . Science . 280 . 5372 . 2112–4 . June 1998 . 9641916 . 10.1126/science.280.5372.2112 .
8. Fukuhara S, Chikumi H, Gutkind JS . RGS-containing RhoGEFs: the missing link between transforming G proteins and Rho? . Oncogene . 20 . 13 . 1661–8 . March 2001 . 11313914 . 10.1038/sj.onc.1204182 . free .
9. Diviani D, Soderling J, Scott JD . AKAP-Lbc anchors protein kinase A and nucleates Galpha 12-selective Rho-mediated stress fiber formation . The Journal of Biological Chemistry . 276 . 47 . 44247–57 . November 2001 . 11546812 . 10.1074/jbc.M106629200 . free .
10. Kozasa T . Regulation of G protein-mediated signal transduction by RGS proteins . Life Sciences . 68 . 19–20 . 2309–17 . April 2001 . 11358341 . 10.1016/S0024-3205(01)01020-7 .
11. Johnson EN, Seasholtz TM, Waheed AA, Kreutz B, Suzuki N, Kozasa T, Jones TL, Brown JH, Druey KM . RGS16 inhibits signalling through the G alpha 13-Rho axis . Nature Cell Biology . 5 . 12 . 1095–103 . December 2003 . 14634662 . 10.1038/ncb1065 . 6798899 .
12. Holinstat M, Mehta D, Kozasa T, Minshall RD, Malik AB . Protein kinase Calpha-induced p115RhoGEF phosphorylation signals endothelial cytoskeletal rearrangement . The Journal of Biological Chemistry . 278 . 31 . 28793–8 . August 2003 . 12754211 . 10.1074/jbc.M303900200 . free .