Src homology 3 domain-containing Guanine nucleotide Exchange Factor)
Identifiers
SymbolSGEF
Alt. symbolsCSGEF, HMFN1864
NCBI gene26084
RefSeqNM_015595
UniProtQ96DR7
Other data
LocusChr. 3 q25.2
Search for
StructuresSwiss-model
DomainsInterPro

SGEF (Src homology 3 domain-containing Guanine nucleotide Exchange Factor) is a 97 kDa protein involved in intracellular signalling networks. It functions as a guanine nucleotide exchange factor (GEF) for RhoG, a small G protein of the Rho family.[1]

Discovery

SGEF was discovered during a screen for androgen-responsive genes in human prostate cancer cells.[2] Subsequent northern blot analysis revealed expression of SGEF in tissues of the heart, brain, placenta, lung, liver, kidney, pancreas, prostate, testis, small intestine and colon. SGEF is also expressed in endothelial cells of the vasculature.[3] Several widely used cell lines express this protein, these include A431, HeLa, HUT78, HEK-293, Jurkat, THP, PC12, RAJI, U937 and Meg-01.[4] SGEF was identified to contribute to the formation of atherosclerosis through promoting endothelial docking structures that resulted in retention of leukocytes at athero-prone sites of inflammation.[5] Genetic variants in SGEF have been associated with coronary artery disease[6]

Structure and function

SGEF is part of a large class of proteins (GEFs) that function to activate small G proteins. In their resting state G proteins are bound to guanosine diphosphate (GDP) and their activation requires the dissociation of GDP and binding of guanosine triphosphate (GTP). GEFs activate G proteins by promoting nucleotide exchange.

SGEF has the canonical GEF structure of tandem DH and PH domains, which elicit nucleotide exchange and, in addition, contains an N-terminal proline-rich motif and a C-terminal SH3 domain.[2] Proline regions and SH3 domains often mediate recruitment and binding to adaptor proteins suggesting that SGEF is probably involved in the formation of heteromultimeric protein complexes.

Regulation of activity

Data from several studies suggest that SGEF is regulated by its recruitment to transmembrane receptor-linked adaptor proteins via its SH3 domain. In one study, mutation of the SH3 domain disrupted SGEF-dependent functions in NIH-3T3 fibroblasts.[4] In endothelial cells SGEF was recruited to the intracellular domain of the transmembrane adhesion molecule ICAM-1 upon leukocyte adhesion to the endothelium.[3]

References

  1. ↑ "Entrez Gene: Src homology 3 domain-containing guanine nucleotide exchange factor (SGEF)".
  2. 1 2 Qi H, Fournier A, Grenier J (May 2003). "Isolation of the novel human guanine nucleotide exchange factor Src homology 3 domain-containing guanine nucleotide exchange factor (SGEF) and of C-terminal SGEF, an N-terminally truncated form of SGEF, the expression of which regulated by androgen in prostate cancer cells". Endocrinology. 144 (5): 1742–52. doi:10.1210/en.2002-220984. PMID 12697679.
  3. 1 2 van Buul JD, Allingham MJ, Samson T (September 2007). "RhoG regulates endothelial apical cup assembly downstream from ICAM1 engagement and is involved in leukocyte trans-endothelial migration". J. Cell Biol. 178 (7): 1279–93. doi:10.1083/jcb.200612053. PMC 2064659. PMID 17875742.
  4. 1 2 Ellerbroek SM, Wennerberg K, Arthur WT (July 2004). "SGEF, a RhoG Guanine Nucleotide Exchange Factor that Stimulates Macropinocytosis". Mol. Biol. Cell. 15 (7): 3309–19. doi:10.1091/mbc.E04-02-0146. PMC 452585. PMID 15133129.
  5. ↑ Samson et al 2013 "The Guanine-Nucleotide Exchange Factor SGEF Plays a Crucial Role in the Formation of Atherosclerosis"
  6. ↑ Verweij et al 2017, "Identification of 15 novel risk loci for coronary artery disease and genetic risk of recurrent events, atrial fibrillation and heart failure"
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