Disease relevance of SOS1

• Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome [1].
• A mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1 [2].
• Similar SOS1 deletion constructs are functional in animal models, and a transgenic mouse construct with a comparable SOS1 chimera produces a phenotype with skin hypertrophy [2].
• The solution structure of the pleckstrin homology domain of human SOS1. A possible structural role for the sequential association of diffuse B cell lymphoma and pleckstrin homology domains [3].
• Tumor HGF lacks prognostic significance in Mexican breast cancer patients [4].
• These findings elucidate the mechanisms for gingival overgrowth mediated by SOS1 gene mutation in humans [5].

Psychiatry related information on SOS1

• We found that proteins implicated in signal transduction from cell surface receptors via the ras pathway, namely Grb2 and SOS-1, were altered in cases of Alzheimer's disease in comparison to age-matched controls [6].

High impact information on SOS1

• Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor [1].
• The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth [1].
• Eps8 is a substrate of the EGFR, which is held in a complex with Sos1 by the adaptor protein E3bl (ref. 2), thereby mediating activation of Rac [7].
• Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2 [8].
• {beta}4 integrin activates a Shp2-Src signaling pathway that sustains HGF-induced anchorage-independent growth [9].

Chemical compound and disease context of SOS1

• Our data demonstrate that the development of fulvestrant resistance in two breast cancer cell lines, MCF7 and T47D, is accompanied by an augmented migratory and invasive phenotype in vitro and overexpression of the HGF/SF receptor, c-Met [10].
• As part of our studies to identify the gene responsible for hereditary gingival fibromatosis, GINGF (OMIM 135300), we have identified and cloned a novel human gene that contains the highly conserved methyltransferase domain characteristic of S-adenosylmethionine-dependent methyltransferases [11].

Biological context of SOS1

• The SH3 domains of Grb2 form a stable complex with SOS1 and two proteins of 75 kD and 120 kD, which undergo tyrosine phosphorylation in Fc gamma RIIA stimulated cells [12].
• The SOS3-SOS2 kinase complex regulates the expression and activity of ion transporters such as SOS1 to re-establish cellular ionic homeostasis under salinity [13].
• An autosomal dominant form of hereditary gingival fibromatosis (HGF, MIM 135300) was recently mapped to chromosome 2p21 in a large Brazilian family and there was an earlier report of GF in a boy with a cytogenetic duplication involving 2p13-->p21 [14].
• Molecular cytogenetic analysis of the 2p13-->p21 duplication associated with GF showed that the duplicated region was proximal to the candidate interval for HGF [14].
• To test evidence of increased cell proliferation, we studied histological, morphological, and proliferation characteristics in monolayer and three-dimensional cultures of fibroblasts with the SOS1 g.126,142-126,143insC mutation [15].

Anatomical context of SOS1

• The protein kinase complex then phosphorylates and activates various ion transporters, such as the plasma membrane Na(+)/H(+) antiporter SOS1 [16].
• Expression of alternative forms of Ras exchange factors GRF and SOS1 in different human tissues and cell lines [17].
• Stimulation of Jurkat cells with either anti-TCR beta or anti-CD3 monoclonal antibody failed to induce substantial tyrosine phosphorylation of Shc proteins or their association with Grb2 which forms a complex with the guanine nucleotide exchange factor hSOS [18].
• To demonstrate the practical potential and limitations of global analyses of ITC titrations for the study of cooperative multiprotein interactions, we have examined the interactions of three proteins that are critical for signal transduction after T-cell activation, LAT, Grb2, and Sos1 [19].
• Hepatocyte growth factor-scatter factor (HGF-SF) is a pleiotropic protein implicated in tumor formation and metastasis [4].

Associations of SOS1 with chemical compounds

• In this report, we describe the genomic structure of the SOS1 gene and present evidence that insertion of a cytosine between nucleotides 126,142 and 126,143 in codon 1083 of the SOS1 gene is responsible for HGF1 [2].
• The human SOS1 PH domain binds to inositol 1,4,5-triphosphate with a approximately 60 mu M affinity [3].
• The phosphorylation of growth factor receptor by VK3 was indicated to be functional, since these were connected with growth factor receptor-bound protein 2 (Grb2) and SOS1 [20].
• The carboxyl-terminal proline-rich domain of SOS1 is involved in the interaction with the PLC-gamma1 SH3 domain [21].
• The activation of many hematopoietic cells via cytokine receptors, as well as B and T cell receptors, leads to the tyrosine phosphorylation of Shc and its association with both Grb2-Sos1 complexes and with a 145 kDa protein referred to as the SH2 containing inositol 5-phosphatase (SHIP1) [22].

Physical interactions of SOS1

• This insertion mutation, which segregates in a dominant manner over four generations, introduces a frameshift and creates a premature stop codon, abolishing four functionally important proline-rich SH3 binding domains normally present in the carboxyl-terminal region of the SOS1 protein [2].
• The membrane immunoglobulin receptor utilizes a Shc/Grb2/hSOS complex for activation of the mitogen-activated protein kinase cascade in a B-cell line [23].

Regulatory relationships of SOS1

• Identification of the mitogen-activated protein kinase phosphorylation sites on human Sos1 that regulate interaction with Grb2 [24].

Other interactions of SOS1

• Mammalian cells contain two related but distinct Sos proteins, Sos1 and Sos2 [25].
• The expression of p21Ras and its regulatory proteins; hSOS1 and p120GAP were studied [26].
• Insulin-dependent translocation of Shc, SOS1, and MAPK to lipid raft microdomains was markedly attenuated by FLNa expression [27].
• Although the mechanisms of Ras GEF regulation are unclear, recent studies suggest that translocation of SOS1 to the plasma membrane, where Ras is located, might be responsible for Ras activation [28].
• Decreased expression of the p21ras stimulatory factor hSOS in PBMC from inactive SLE patients [29].

Analytical, diagnostic and therapeutic context of SOS1

• Disease-free survival and overall survival were similar between the high tumor HGF group of patients and the low HGF patients (p = 0.7 and p = 0.36 respectively) [4].
• Primary breast cancer tissue HGF-SF was measured by quantitative sandwich enzyme immunoassay [4].
• Purified, bacterially expressed PH domains of Sos1, IRS-1, betaARK, and PLCdelta1 were analyzed functionally by means of microinjection into full grown, stage VI Xenopus laevis oocytes [30].
• Consistent with the variety of transcripts detected, several protein forms were also identified in Western immunoblots with antisera raised against specific domains of hSOS1 and human Ras-GRF gene products [17].
• Sequence analyses of C2orf8 excluded coding region mutations as causative of GINGF [11].

References