Incell signalling,Son of Sevenless (SOS) refers to a set of genes encodingguanine nucleotide exchange factors that act on theRas subfamily ofsmall GTPases.

The gene was so named because the Sos protein that it encoded was found to operate downstream of thesevenless gene inDrosophila melanogaster in aRas/MAP kinase pathway.^[1] Whensevenless is mutated or otherwise dysfunctional during development of the fly'sultraviolet light-sensitivecompound eye, the seventh, central photoreceptor (R7) of eachommatidium fails to form.^[2][3] Similarly, the mammalianorthologues of Sos,SOS1 and SOS2, function downstream of many growth factor and adhesion receptors.

Ras-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 thathydrolyses 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 boundnucleotide (usually GDP). Once released from SOS, the Ras-GTPase quickly binds fresh guanine nucleotide from thecytosol. 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 theRasGAP family, which bind to Ras and increase itscatalytic rate by a factor of one thousand - in effect, increasing the rate at which Ras is inactivated.

Dominant mutantalleles of SOS1 have recently been found to causeNoonan syndrome^[4] and hereditarygingival fibromatosis type 1.^[5] Noonan syndrome has also been shown to be caused by mutations inKRAS andPTPN11 genes.^[6] 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.^[7]

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 anauto-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 SOS1 alleles encoding hyper-activated and dysregulated variants of the protein.

• SOS1+Protein at the U.S. National Library of MedicineMedical Subject Headings (MeSH)
• ExPASy Proteomics Server: SOS

• Genes on human chromosome 2
• Genes on human chromosome 14
• GTP-binding protein regulators
• Proteins

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