Incell signalling,Son of Sevenless(SOS) refers to a set of genes encodingguanine nucleotide exchange factorsthat act on theRas subfamilyofsmall GTPases.
| son of sevenless homolog 1 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | SOS1 | ||||||
| Alt. symbols | GINGF | ||||||
| NCBI gene | 6654 | ||||||
| HGNC | 11187 | ||||||
| OMIM | 182530 | ||||||
| RefSeq | NM_005633 | ||||||
| UniProt | Q07889 | ||||||
| Other data | |||||||
| Locus | Chr. 2p21 | ||||||
| |||||||
| son of sevenless homolog 2 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | SOS2 | ||||||
| NCBI gene | 6655 | ||||||
| HGNC | 11188 | ||||||
| OMIM | 601247 | ||||||
| RefSeq | NM_006939 | ||||||
| UniProt | Q07890 | ||||||
| Other data | |||||||
| Locus | Chr. 14q21 | ||||||
| |||||||
History and name
editThe gene was so named because the Sos protein that it encoded was found to operate downstream of thesevenlessgene inDrosophila melanogasterin aRas/MAP kinase pathway.[1]Whensevenlessis mutated or otherwise dysfunctional during development of the fly'sultraviolet light-sensitivecompound eye,the seventh, central photoreceptor (R7) of eachommatidiumfails to form.[2][3]Similarly, the mammalianorthologuesof Sos,SOS1and SOS2, function downstream of many growth factor and adhesion receptors.
Function
editRas-GTPases act as molecular switches that bind to downstream effectors, such as the protein kinasec-Raf,and localise them to the membrane, resulting in their activation. Ras-GTPases are considered inactive when bound toguanosine diphosphate(GDP), and active when bound toguanosine triphosphate(GTP). As the name implies, Ras-GTPases possess intrinsic enzymatic activity that hydrolyses GTP to GDP and phosphate. Thus, upon binding to GTP, the duration of Ras-GTPase activity depends on the rate of hydrolysis. SOS (and other guanine nucleotide exchange factors) act by binding Ras-GTPases and forcing them to release their bound nucleotide (usually GDP). Once released from SOS, the Ras-GTPase quickly binds fresh guanine nucleotide from the cytosol. Since GTP is roughly ten times more abundant than GDP in thecytosol,this usually results in Ras activation. The normal rate of Ras catalytic GTPase (GTP hydrolysis) activity can be increased by proteins of theRasGAPfamily, which bind to Ras and increase its catalytic rate by a factor of one thousand - in effect, increasing the rate at which Ras is inactivated.
Genetic diseases associated with SOS1
editDominant mutant alleles of SOS1 have recently been found to causeNoonan syndrome[4]and hereditary gingival fibromatosis type 1.[5]Noonan syndrome has also been shown to be caused by mutations inKRASandPTPN11genes.[6]A common feature of these genes is that their products have all been strongly implicated as positive regulators of the Ras/MAP kinasesignal transduction pathway. Therefore, it is thought that dysregulation of this pathway during development is responsible for many of the clinical features of this syndrome.[7]
Noonan syndromemutations in SOS1 are distributed in clusters positioned throughout the SOS1 coding region. Biochemically, these mutations have been shown to similarly effect aberrant activation of the catalytic domain towards Ras-GTPases. This may be explained because the SOS1 protein adopts an auto-inhibited conformation dependent on multiple domain-to-domain interactions that cooperate to block access of the SOS1 catalytic core to its Ras-GTPase targets.[8]The mutations that cause Noonan syndrome thus appear to perturb intramolecular interactions necessary for SOS1 auto-inhibition. In this way these mutations are thought to create SOS1allelesencoding hyper-activated and dysregulated variants of the protein.
References
edit- ^Rogge RD, Karlovitch CA, Banerjee U (January 1991)."Genetic Dissection of a Neurodevelopmental Pathway: Son of sevenless Functions Downstream of the sevenless and EGF Receptor Tyrosine Kinases".Cell.64(1): 39–48.doi:10.1016/0092-8674(91)90207-F.PMID1846090.S2CID34466759.
- ^Simon MA, Dodson GS, Rubin GM (April 1993). "An SH3-SH2-SH3 protein is required for p21Ras1 activation and binds to sevenless and Sos proteins in vitro".Cell.73(1): 169–77.doi:10.1016/0092-8674(93)90169-Q.PMID8462097.S2CID38668180.
- ^Nimnual A, Bar-Sagi D (August 2002). "The two hats of SOS".Sci. STKE.2002(145): PE36.doi:10.1126/stke.2002.145.pe36.PMID12177507.S2CID43828427.
- ^Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, Li L, Yassin Y, Tamburino AM, Neel BG, Kucherlapati RS (January 2007). "Germline gain-of-function mutations in SOS1 cause Noonan syndrome".Nat. Genet.39(1): 70–4.doi:10.1038/ng1926.PMID17143285.S2CID10222262.
- ^Hart TC, Zhang Y, Gorry MC, Hart PS, Cooper M, Marazita ML, Marks JM, Cortelli JR, Pallos D (April 2002)."A mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1".Am. J. Hum. Genet.70(4): 943–54.doi:10.1086/339689.PMC379122.PMID11868160.
- ^Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD (December 2001). "Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome".Nat. Genet.29(4): 465–8.doi:10.1038/ng772.PMID11704759.S2CID14627986.
- ^Bentires-Alj M, Kontaridis MI, Neel BG (March 2006). "Stops along the RAS pathway in human genetic disease".Nat. Med.12(3): 283–5.doi:10.1038/nm0306-283.PMID16520774.S2CID6989331.
- ^Sondermann H, Soisson SM, Boykevisch S, Yang SS, Bar-Sagi D, Kuriyan J (October 2004)."Structural analysis of autoinhibition in the Ras activator Son of sevenless".Cell.119(3): 393–405.doi:10.1016/j.cell.2004.10.005.PMID15507210.S2CID14786628.
External links
edit- SOS1+Proteinat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
- ExPASy Proteomics Server: SOS