Understanding SOS (Son of Sevenless)

Abstract

Son of Sevenless (SOS) was discovered in Drosophila melanogaster. Essential for normal eye development in Drosophila, SOS has two human homologues, SOS1 and SOS2. The SOS1 gene encodes the Son of Sevenless 1 protein, a Ras and Rac guanine nucleotide exchange factor. This protein is composed of several important domains. The CDC25 and REM domains provide the catalytic activity of SOS1 towards Ras and the histone fold DH/PH (Dbl homology and Pleckstrin homology) domains function, in tandem, to stimulate GTP/GDP exchange for Rac. In contrast to Ras, there have been few studies that implicate SOS1 in human disease and, initially, less attention was given to this gene. However, mutations in SOS1 have been reported recently in Noonan syndrome and in type 1 hereditary gingival fibromatosis. Although, there have been very few studies that focus on the regulation of this important gene by physiological or exogenous factors, we recently found that the SOS1 gene was induced by the environmental toxin, dioxin, and that this effect was mediated by the aryl hydrocarbon receptor (AhR). These recent observations raise the possibility that alterations in the expression of the SOS1 gene and, consequently, in the activity of the SOS1 protein may affect toxicological endpoints and lead to clinical disease. These possibilities, thus, have stimulated much interest in SOS1 recently. In this article, we review the functions of SOS1 and the evidence for its roles in physiology and pathology across species.

EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells

“…Growth factor-induced phosphorylation of serine/threonine residues of SOS1, mediated by MAP kinases, alters its association with GRB2 and inhibits its function, providing a negative feedback mechanism (45)(46)(47). SOS1 has been reported to be involved in several different cancers including breast cancer, hematological malignancies, and skin cancer (23). Amplification of GRB2 and SOS1 has been reported in bladder cancer (48), and overexpression of SOS1 has been seen in prostate (49) and kidney cancer cells (50).…”

“…The full coding sequence of SOS1 translates to 1,333 amino acids, of which 355 residues of the N terminus were lost in the truncated protein driven by the inserted promoter. However, the portion of SOS1 remaining retains the catalytic domain (23). Using a 5′ VBIM-specific primer and a 3′ gene-specific primer, analysis by RT-PCR showed overexpression of the truncated SOS1 mRNA in erlotinibresistant SD3.1 cells, and expression of CRE recombinase eliminated this expression (Fig.…”

Differential allelic expression of SOS1 and hyperexpression of the activating SOS1 c.755C variant in a Noonan syndrome family

“…The SOS1 DH domain interacting with the PH domain both inhibits exchange activity for RAC1 and promotes the interaction with the cell membrane inhibiting RAS activation. 15 As the SOS1 c.755T4C variation has been recently reported also in a healthy subject (http://www.1000genomes.org), its role in activating the RAS pathway needed to be demonstrated. Furthermore, a study based on NMR methodology aimed at detecting defects in RAS GTPase cycling showed that p.I252T variant failed to stimulate ERK activation in serum-activated cells, whereas the assays carried out in solution allowed to detect ERK hyperactivation.…”

“…SOS1 is also known to activate a distinct pathway mediated by RAC1, a GTPase belonging to the Rho-family. 15 Ile252 is an invariant residue in a hydrophobic core of the SOS1 DH domain that, competing with RAS for binding to the allosteric site, might act as an intramolecular inhibitor of RAS-GEF activity. 16 Bioinformatic analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) identified the p.(I252T) variant as 'probably damaging' with a score of 0.674 and the analysis with SIFT predicted the amino-acid change to 'affect protein function', given that the Ile residue is highly conserved during evolution.…”

Combined Rational Design and a High Throughput Screening Platform for Identifying Chemical Inhibitors of a Ras-activating Enzyme

“…UC-773587 and UC-857993 Inhibit Ras Signaling and Cancer Cell Growth-To assess cellular activity, the two SOS1 inhibitors (UC-773587 and UC-857993) were tested in cells at inhibiting epidermal growth factor receptor (EGFR)-mediated Ras activation and downstream ERK activation (35,36). Therefore, we serum-starved NIH/3T3 mouse fibroblasts and pretreated them with either UC-773587 or UC-857993.…”