ARHGEF12

ARHGEF12
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1TXD, 1X86, 2OMJ, 2OS6
Identifiers
Aliases	ARHGEF12, LARG, PRO2792, Rho guanine nucleotide exchange factor 12
External IDs	OMIM: 604763 MGI: 1916882 HomoloGene: 9088 GeneCards: ARHGEF12
Gene location (Human)
Chr.	Chromosome 11 (human)[1]
End	120,489,937 bp[1]
Gene location (Mouse)
Chr.	Chromosome 9 (mouse)[2]
End	43,107,239 bp[2]
RNA expression pattern
	; ; ; ;
	More reference expression data
Gene ontology
Molecular function	• GO:0001948 protein binding; • G-protein coupled receptor binding; • GTPase activator activity; • guanyl-nucleotide exchange factor activity; • Rho guanyl-nucleotide exchange factor activity;
Cellular component	• cytoplasm; • cytosol; • extracellular exosome; • membrane;
Biological process	• positive regulation of GTPase activity; • regulation of Rho protein signal transduction; • intracellular signal transduction; • regulation of small GTPase mediated signal transduction; • positive regulation of apoptotic process; • G-protein coupled receptor signaling pathway; • regulation of molecular function; • Rho protein signal transduction;
	Sources:Amigo / QuickGO
Orthologs
	23365
	69632
	ENSG00000196914
	ENSMUSG00000059495
	Q9NZN5
	Q8R4H2
	NM_001198665; NM_001301084; NM_015313
	NM_027144; NM_001359232
	NP_001185594; NP_001288013; NP_056128
	NP_081420; NP_001346161
	Wikidata
View/Edit Human	View/Edit Mouse

Rho guanine nucleotide exchange factor 12 is a protein that in humans is encoded by the ARHGEF12 gene.[5][6][7] This protein is also called RhoGEF12 or Leukemia-associated Rho guanine nucleotide exchange factor (LARG).

Function

Rho guanine nucleotide exchange factor 12 is guanine nucleotide exchange factor (GEF) for the RhoA small GTPase protein. [5] 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.[8] In particular, active Rho is a major regulator of the cell 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] The others are ARHGEF1 (also known as p115-RhoGEF), ARHGEF11 (also known as PDZ-RhoGEF) and AKAP13 (also known as ARHGEF13 and Lbc). [10][11] GPCR-regulated RhoGEF12 (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.[12]

Clinical significance

This protein is observed to form myeloid/lymphoid fusion partner in acute myeloid leukemia.[7]

Interactions

ARHGEF12 has been shown to interact with:

GNA12,[13][14]
GNA13,[13][14]
IGF1R,[15]
PLXNB1,[16]
RHOA,[14][17] and
TEC.[14]

References

GRCh38: Ensembl release 89: ENSG00000196914 - Ensembl, May 2017
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.
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. 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.
"Entrez Gene: ARHGEF12 Rho guanine nucleotide exchange factor (GEF) 12".
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.
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. doi:10.1016/S0014-5793(00)02224-9. PMID 11094164.
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. 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.

External links

Human ARHGEF12 genome location and ARHGEF12 gene details page in the UCSC Genome Browser.

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[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000196914 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000059495 - Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid10681437-5] 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. doi:10.1073/pnas.040569197. PMC 15768. PMID 10681437.

[pmid9205841-6] 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.

[entrez-7] "Entrez Gene: ARHGEF12 Rho guanine nucleotide exchange factor (GEF) 12".

[”pmid24183240”-8] 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.

[”pmid12024019”-9] 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.

[pmid11313914-10] 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.

[”pmid11546812”-11] 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.

[”pmid11358341”-12] 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.

[pmid11094164-13] 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. doi:10.1016/S0014-5793(00)02224-9. PMID 11094164.

[pmid12515866-14] 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. doi:10.1073/pnas.0234057100. PMC 141065. PMID 12515866.

[pmid11724822-15] 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.

[pmid12220504-16] 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.

[pmid11373293-17] 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.