SGEF

Last updated
Src homology 3 domain-containing Guanine nucleotide Exchange Factor)
Identifiers
SymbolSGEF
Alt. symbolsCSGEF, HMFN1864
NCBI gene 26084
RefSeq NM_015595
UniProt Q96DR7
Other data
Locus Chr. 3 q25.2

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]

Contents

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]

Related Research Articles

GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a protein domain common to many GTPases.

Small GTPases, also known as small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotrimeric G-proteins, but unlike the alpha subunit of G proteins, a small GTPase can function independently as a hydrolase enzyme to bind to and hydrolyze a guanosine triphosphate (GTP) to form guanosine diphosphate (GDP). The best-known members are the Ras GTPases and hence they are sometimes called Ras subfamily GTPases.

Guanine nucleotide exchange factor Proteins which remove GDP from GTPases

Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity. Some GEFs can activate multiple GTPases while others are specific to a single GTPase.

Adapter molecule crk Protein-coding gene in the species Homo sapiens

Adapter molecule crk also known as proto-oncogene c-Crk is a protein that in humans is encoded by the CRK gene.

FGD1 Protein-coding gene in the species Homo sapiens

FYVE, RhoGEF and PH domain-containing protein 1 (FGD1) also known as faciogenital dysplasia 1 protein (FGDY), zinc finger FYVE domain-containing protein 3 (ZFYVE3), or Rho/Rac guanine nucleotide exchange factor FGD1 is a protein that in humans is encoded by the FGD1 gene that lies on the X chromosome. Orthologs of the FGD1 gene are found in dog, cow, mouse, rat, and zebrafish, and also budding yeast and C. elegans. It is a member of the FYVE, RhoGEF and PH domain containing family.

RAPGEF1

Rap guanine nucleotide exchange factor 1 is a protein that in humans is encoded by the RAPGEF1 gene.

RhoGEF domain

RhoGEF domain describes two distinct structural domains with guanine nucleotide exchange factor (GEF) activity to regulate small GTPases in the Rho family. Rho small GTPases are inactive when bound to GDP but active when bound to GTP; RhoGEF domains in proteins are able to promote GDP release and GTP binding to activate specific Rho family members, including RhoA, Rac1 and Cdc42.

ARHGEF7 Protein-coding gene in the species Homo sapiens

Rho guanine nucleotide exchange factor 7 is a protein that in humans is encoded by the ARHGEF7 gene.

AKAP13

A-kinase anchor protein 13 is an protein that in humans is encoded by the AKAP13 gene. This protein is also called AKAP-Lbc because it encodes the lymphocyte blast crisis (Lbc) oncogene, and ARHGEF13/RhoGEF13 because it contains a guanine nucleotide exchange factor (GEF) domain for the RhoA small GTP-binding protein.

Dock180

Dock180, also known as DOCK1, is a large protein involved in intracellular signalling networks. It is the mammalian ortholog of the C. elegans protein CED-5 and belongs to the DOCK family of Guanine nucleotide exchange factors (GEFs).

ARHGEF1 Protein-coding gene in the species Homo sapiens

Rho guanine nucleotide exchange factor 1 is a protein that in humans is encoded by the ARHGEF1 gene. This protein is also called RhoGEF1 or p115-RhoGEF.

ARHGEF11

Rho guanine nucleotide exchange factor 11 is a protein that in humans is encoded by the ARHGEF11 gene. This protein is also called RhoGEF11 or PDZ-RhoGEF.

RhoG

RhoG is a small monomeric GTP-binding protein, and is an important component of many intracellular signalling pathways. It is a member of the Rac subfamily of the Rho family of small G proteins and is encoded by the gene RHOG.

TRIO (gene)

Triple functional domain protein is a protein that in humans is encoded by the TRIO gene.

Dock2

Dock2, also known as DOCK2, is a large protein involved in intracellular signalling networks. It is a member of the DOCK-A subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G proteins. Dock2 specifically activates isoforms of the small G protein Rac.

VAV3 Protein-coding gene in the species Homo sapiens

Guanine nucleotide exchange factor VAV3 is a protein that in humans is encoded by the VAV3 gene.

Dock4 Protein-coding gene in the species Homo sapiens

Dock4, also known as DOCK4, is a large protein involved in intracellular signalling networks. It is a member of the DOCK-B subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G proteins. Dock4 activates the small G proteins Rac and Rap1.

Dock3

Dock3, also known as MOCA and PBP, is a large protein involved in intracellular signalling networks. It is a member of the DOCK-B subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G proteins. Dock3 specifically activates the small G protein Rac.

Dock9

Dock9, also known as Zizimin1, is a large protein involved in intracellular signalling networks. It is a member of the DOCK-D subfamily of the DOCK family of guanine nucleotide exchange factors that function as activators of small G proteins. Dock9 activates the small G protein Cdc42.

ELMO is a family of related proteins involved in intracellular signalling networks. These proteins have no intrinsic catalytic activity and instead function as adaptors which can regulate the activity of other proteins through their ability to mediate protein-protein interactions.

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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