High impact information on Sos1

• We propose a model in which Eps8 mediates the transfer of signals between Ras and Rac, by forming a complex with E3b1 and Sos-1 [1].
• We have investigated the role of the mammalian Son of sevenless 1 (Sos1) protein in growth factor signaling in vivo by generating mice and cell lines that lacked the Sos1 protein [2].
• To address the specificity or redundancy of these exchange factors, we have generated Sos1/Sos2 double- or RasGRP3-deficient B cell lines and determined their ability to mediate Ras activation upon B cell receptor (BCR) stimulation [3].
• Impaired plasma membrane targeting of Grb2-murine son of sevenless (mSOS) complex and differential activation of the Fyn-T cell receptor (TCR)-zeta-Cbl pathway mediate T cell hyporesponsiveness in autoimmune nonobese diabetic mice [4].
• These findings implicate mSOS as an important mediator of downregulation of Ras signaling in hyporesponsive NOD T cells [4].

Biological context of Sos1

• Finally, we show that Vav1 is required for TCR-induced LAT phosphorylation, a key event for the activation of both phospholipase Cgamma1 and Sos1/2 [5].
• Targeted disruption of both alleles of mouse sos1, which encodes a Ras-specific exchange factor, conferred mid-gestational embryonic lethality that was secondary to impaired placental development and was associated with very low placental ERK activity [6].
• Although an msos1 plasmid did not induce phenotypic changes in NIH 3T3 cells, addition of a 15-codon myristoylation signal to its 5' end enabled the resulting plasmid, myr-sos1, to induce approximately one-half as many foci of transformed cells as a v-H-ras control [7].
• This binding site is contained within the peptide N20, which corresponds to amino acids 1143-1162 of Sos1 [8].
• Whilst the association of Sos1 and Grb2 following EGF stimulation is not cell type specific, we find that it is dependent on cell density and that the response to EGF differs to that induced by NGF [9].

Anatomical context of Sos1

• The trophoblastic layers of sos1(-/-) embryos were poorly developed, correlating with high sos1 expression in wild-type trophoblasts [6].
• We investigated the functional and physical interaction between mSOS and Fyn in T-cell hybridoma cells [10].
• The activation of all three delta Raf:ER proteins in 3T3 cells led to the hyperphosphorylation of the resident p74raf-1 and mSOS1 proteins, suggesting the possibility of "cross-talk" between the different Raf kinases and feedback regulation of intracellular signaling pathways [11].

Associations of Sos1 with chemical compounds

• Fms also formed complexes with Grb2 and Sos1, and neither contained phosphotyrosine [12].
• Vav and Sos1 are Dbl family guanine nucleotide exchange factors, which activate Rho family GTPases in response to phosphatidylinositol 3-kinase products [13].
• Grb2 is an adaptor protein that links receptor and cytoplasmic tyrosine kinases to the Ras signalling pathway by binding the Ras-specific guanine nucleotide exchange factor, Sos1, through its SH3 domains [8].
• Inhibition studies with BIAcore using proline rich peptides derived from the C-terminus of Sos1 show that there is a single major binding site for Grb2 in Sos1 [8].

Enzymatic interactions of Sos1

• In addition, inhibition of mSOS phosphorylation did not affect complex formation of mSOS with tyrosine phosphorylated Shc [14].

Regulatory relationships of Sos1

• Catalytic activity of the mouse guanine nucleotide exchanger mSOS is activated by Fyn tyrosine protein kinase and the T-cell antigen receptor in T cells [10].

Other interactions of Sos1

• Second, Vav1 is required for recruitment of Sos1 and -2 to the transmembrane adapter protein LAT [5].
• Immunoblot analysis of these precipitates revealed that insulin causes a marked hyperphosphorylation of Sos1 and a 50% decrease in Grb2 associated with Sos proteins under these conditions [15].
• Lysates of such desensitized cells were quantitatively immunoprecipitated with an antiserum recognizing both Sos1 and Sos2 proteins or a specific anti-Sos2 antiserum [15].
• In mSOS immunoprecipitates, Shc could be detected as well [16].
• Here we report that mutations within the switch 2 domain of Ras (residues 62-69) inhibit activation of Ras by the mammalian GEFs, Sos1, and GRF/CDC25Mm [17].

Analytical, diagnostic and therapeutic context of Sos1

• A 19 kDa protein was identified to associate with the Dbl oncogene homology domain of Sos1 (Sos-DH) and was purified from rat brains by GST-Sos-DH affinity chromatography [18].
• In situ hybridization shows that SOS1 maps to 2p22-->p16 and SOS2 to 14q21-->q22 in the human genome [19].
• We have investigated the effects of AgR ligation on three proteins that have been implicated as regulators of Ras: SHC, GRB-2, and mSOS1 [20].

References