Rho guanine nucleotide exchange factor 12 is a protein that in humans is encoded by the ARHGEF12 gene .[ 5] [ 6] [ 7]
Rho guanine nucleotide exchange factor 12 is guanine nucleotide exchange factor (GEF) for the RhoA small GTPase protein. [ 5] 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.[ 8] actin cytoskeleton .[ 8]
RhoGEF12 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 .[ 9] ARHGEF1 (also known as p115-RhoGEF), ARHGEF11 (also known as PDZ-RhoGEF) and AKAP13 (also known as ARHGEF13 and Lbc). [ 10] [ 11] 12 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.[ 12]
Clinical significance
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ARHGEF12 has been shown to interact with:
^ a b c GRCh38: Ensembl release 89: ENSG00000196914 – Ensembl , May 2017^ a b c GRCm38: Ensembl release 89: ENSMUSG00000059495 – Ensembl , May 2017^ "Human PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .^ "Mouse PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .^ a b Kourlas PJ, Strout MP, Becknell B, Veronese ML, Croce CM, Theil KS, et al. (February 2000). "Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor: evidence for its fusion with MLL in acute myeloid leukemia" . Proceedings of the National Academy of Sciences of the United States of America . 97 (5): 2145–50. Bibcode :2000PNAS...97.2145K . doi :10.1073/pnas.040569197 PMC 15768 PMID 10681437 . ^ Nagase T, Ishikawa K, Nakajima D, Ohira M, Seki N, Miyajima N, et al. (April 1997). "Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro" . DNA Research . 4 (2): 141–50. doi :10.1093/dnares/4.2.141 PMID 9205841 . ^ a b "Entrez Gene: ARHGEF12 Rho guanine nucleotide exchange factor (GEF) 12" .^ a b Thumkeo D, Watanabe S, Narumiya S (October–November 2013). "Physiological roles of Rho and Rho effectors in mammals". European Journal of Cell Biology . 92 (10–11): 303–15. doi :10.1016/j.ejcb.2013.09.002 . PMID 24183240 . ^ Booden MA, Siderovski DP, Der CJ (June 2002). "Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA" . Molecular and Cellular Biology . 22 (12): 4053–61. doi :10.1128/mcb.22.12.4053-4061.2002 . PMC 133844 PMID 12024019 . ^ Fukuhara S, Chikumi H, Gutkind JS (March 2001). "RGS-containing RhoGEFs: the missing link between transforming G proteins and Rho?" . Oncogene . 20 (13): 1661–8. doi :10.1038/sj.onc.1204182 PMID 11313914 . ^ Diviani D, Soderling J, Scott JD (November 2001). "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. doi :10.1074/jbc.M106629200 PMID 11546812 . ^ Kozasa T (April 2001). "Regulation of G protein-mediated signal transduction by RGS proteins". Life Sciences . 68 (19–20): 2309–17. doi :10.1016/S0024-3205(01)01020-7 . PMID 11358341 . ^ a b Fukuhara S, Chikumi H, Gutkind JS (November 2000). "Leukemia-associated Rho guanine nucleotide exchange factor (LARG) links heterotrimeric G proteins of the G(12) family to Rho" . FEBS Letters . 485 (2–3): 183–8. Bibcode :2000FEBSL.485..183F . doi :10.1016/S0014-5793(00)02224-9 PMID 11094164 . S2CID 7300556 . ^ a b c d Suzuki N, Nakamura S, Mano H, Kozasa T (January 2003). "Galpha 12 activates Rho GTPase through tyrosine-phosphorylated leukemia-associated RhoGEF" . Proceedings of the National Academy of Sciences of the United States of America . 100 (2): 733–8. Bibcode :2003PNAS..100..733S . doi :10.1073/pnas.0234057100 PMC 141065 PMID 12515866 . ^ Taya S, Inagaki N, Sengiku H, Makino H, Iwamatsu A, Urakawa I, et al. (November 2001). "Direct interaction of insulin-like growth factor-1 receptor with leukemia-associated RhoGEF" . The Journal of Cell Biology . 155 (5): 809–20. doi :10.1083/jcb.200106139 . PMC 2150867 PMID 11724822 . ^ Hirotani M, Ohoka Y, Yamamoto T, Nirasawa H, Furuyama T, Kogo M, et al. (September 2002). "Interaction of plexin-B1 with PDZ domain-containing Rho guanine nucleotide exchange factors". Biochemical and Biophysical Research Communications . 297 (1): 32–7. doi :10.1016/S0006-291X(02)02122-8 . PMID 12220504 . ^ Reuther GW, Lambert QT, Booden MA, Wennerberg K, Becknell B, Marcucci G, et al. (July 2001). "Leukemia-associated Rho guanine nucleotide exchange factor, a Dbl family protein found mutated in leukemia, causes transformation by activation of RhoA" . The Journal of Biological Chemistry . 276 (29): 27145–51. doi :10.1074/jbc.M103565200 PMID 11373293 .
Fukuhara S, Chikumi H, Gutkind JS (November 2000). "Leukemia-associated Rho guanine nucleotide exchange factor (LARG) links heterotrimeric G proteins of the G(12) family to Rho" . FEBS Letters . 485 (2–3): 183–8. Bibcode :2000FEBSL.485..183F . doi :10.1016/S0014-5793(00)02224-9 PMID 11094164 . S2CID 7300556 . Reuther GW, Lambert QT, Booden MA, Wennerberg K, Becknell B, Marcucci G, et al. (July 2001). "Leukemia-associated Rho guanine nucleotide exchange factor, a Dbl family protein found mutated in leukemia, causes transformation by activation of RhoA" . The Journal of Biological Chemistry . 276 (29): 27145–51. doi :10.1074/jbc.M103565200 PMID 11373293 . Taya S, Inagaki N, Sengiku H, Makino H, Iwamatsu A, Urakawa I, et al. (November 2001). "Direct interaction of insulin-like growth factor-1 receptor with leukemia-associated RhoGEF" . The Journal of Cell Biology . 155 (5): 809–20. doi :10.1083/jcb.200106139 . PMC 2150867 PMID 11724822 . Chikumi H, Fukuhara S, Gutkind JS (April 2002). "Regulation of G protein-linked guanine nucleotide exchange factors for Rho, PDZ-RhoGEF, and LARG by tyrosine phosphorylation: evidence of a role for focal adhesion kinase" . The Journal of Biological Chemistry . 277 (14): 12463–73. doi :10.1074/jbc.M108504200 PMID 11799111 . Perrot V, Vazquez-Prado J, Gutkind JS (November 2002). "Plexin B regulates Rho through the guanine nucleotide exchange factors leukemia-associated Rho GEF (LARG) and PDZ-RhoGEF" . The Journal of Biological Chemistry . 277 (45): 43115–20. doi :10.1074/jbc.M206005200 PMID 12183458 . Aurandt J, Vikis HG, Gutkind JS, Ahn N, Guan KL (September 2002). "The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG" . Proceedings of the National Academy of Sciences of the United States of America . 99 (19): 12085–90. Bibcode :2002PNAS...9912085A . doi :10.1073/pnas.142433199 PMC 129402 PMID 12196628 . 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"Crystal structures of Delta1-piperideine-2-carboxylate/Delta1-pyrroline-2-carboxylate reductase belonging to a new family of NAD(P)H-dependent oxidoreductases: conformational change, substrate recognition, and stereochemistry of the reaction" . The Journal of Biological Chemistry . 280 (49): 40875–84. doi :10.1074/jbc.M507399200 PMID 16192274 . Bourguignon LY, Gilad E, Brightman A, Diedrich F, Singleton P (May 2006). "Hyaluronan-CD44 interaction with leukemia-associated RhoGEF and epidermal growth factor receptor promotes Rho/Ras co-activation, phospholipase C epsilon-Ca2+ signaling, and cytoskeleton modification in head and neck squamous cell carcinoma cells" . The Journal of Biological Chemistry . 281 (20): 14026–40. doi :10.1074/jbc.M507734200 PMID 16565089 .
