Son of Sevenless

protein
Name = son of sevenless homolog 1 (Drosophila)
caption =


width =
HGNCid = 11187
Symbol = SOS1
AltSymbols = GINGF
EntrezGene = 6654
OMIM = 182530
RefSeq = NM_005633
UniProt = Q07889
PDB =
ECnumber =
Chromosome = 2
Arm = p
Band = 21
LocusSupplementaryData = protein
Name = son of sevenless homolog 2 (Drosophila)
caption =


width =
HGNCid = 11188
Symbol = SOS2
AltSymbols =
EntrezGene = 6655
OMIM = 601247
RefSeq = NM_006939
UniProt = Q07890
PDB =
ECnumber =
Chromosome = 14
Arm = q
Band = 21
LocusSupplementaryData =

In cell signalling, "Son of Sevenless" ("SOS") is a gene encoding a guanine nucleotide exchange factor that acts on Ras-GTPases.

History and name

The gene was so named because the Sos protein that it encoded was found to operate downstream of the "sevenless" gene in "Drosophila melanogaster" in a Ras/MAP kinase pathway. When "sevenless" is mutated or otherwise dysfunctional during development of the fly's ultraviolet light-sensitive compound eye, the seventh, central photoreceptor (R7) of each ommatidium fails to form [Simon MA "et al." Cell 1993;73:169-77] cite journal | author=Nimnual A, Bar-Sagi D | title=The two hats of SOS | journal=Sci STKE | year=2002 | pages=PE36 | volume=2002 | issue=145 | pmid=12177507 ] . Similarly, the mammalian paralogues of Sos, SOS1 and SOS2, function downstream of many growth factor and adhesion receptors.

Function

Ras-GTPases act as molecular switches that bind to downstream effectors, such as the protein kinase c-Raf, and localise them to the membrane resulting in their activation. Ras-GTPases are considered inactive when bound to guanosine diphosphate (GDP), and active when bound to guanosine 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 of 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 the cytosol, this usually results in Ras activation. The normal rate of Ras catalytic GTPase (GTP hydrolysis) activity can be increased by proteins of the RasGAP family, 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

Dominant mutant alleles of SOS1 have recently been found to cause Noonan syndrome [Roberts AE, et al. Nature Genetics Published online: 3 December 2006] and Hereditary Gingival Fibromatosis type 1 [Hart TC Am. J. Hum. Genet. 2002; 70:943–954. Noonan syndrome has also been shown to be caused by mutations in KRAS and PTPN11 genes [Tartaglia M, et al. Nature Genetics 2001;29:465-468] . A common feature of these genes is that their products have all been strongly implicated as positive regulators of the Ras/MAP kinase signal transduction pathway. Therefore it is thought that dysregulation of this pathway during development is responsible for many of the clinical features of this syndrome [Bentires-Alj M, et al. Nat Med. 2006; 12:283-285] .

Noonan syndrome mutations 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 [Sondermann, et al. Cell 2004; 119:393-405] . 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 SOS1 alleles encoding hyper-activated and dysregulated variants of the protein.

References

External links

*
* [http://www.expasy.org/cgi-bin/niceprot.pl?Q07889 ExPASy Proteomics Server: SOS]