sos1 protein


Summary: A mammalian homolog of the DROSOPHILA SON OF SEVENLESS PROTEIN. It is a guanine nucleotide exchange factor for RAS PROTEINS.

Top Publications

  1. Jang S, Lee E, Hart P, Ramaswami M, Pallos D, Hart T. Germ line gain of function with SOS1 mutation in hereditary gingival fibromatosis. J Biol Chem. 2007;282:20245-55 pubmed
    ..These findings elucidate the mechanisms for gingival overgrowth mediated by SOS1 gene mutation in humans. ..
  2. Katso R, Pardo O, Palamidessi A, Franz C, Marinov M, De Laurentiis A, et al. Phosphoinositide 3-Kinase C2beta regulates cytoskeletal organization and cell migration via Rac-dependent mechanisms. Mol Biol Cell. 2006;17:3729-44 pubmed
    ..Taken together, these findings suggest that PI3KC2beta regulates the migration and survival of human tumor cells by distinct molecular mechanisms. ..
  3. Freedman T, Sondermann H, Friedland G, Kortemme T, Bar Sagi D, Marqusee S, et al. A Ras-induced conformational switch in the Ras activator Son of sevenless. Proc Natl Acad Sci U S A. 2006;103:16692-7 pubmed
    ..These results indicate that RasGRF1 lacks the allosteric activation switch that is crucial for Sos activity. ..
  4. Tartaglia M, Gelb B, Zenker M. Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab. 2011;25:161-79 pubmed publisher
    ..Here, we provide an overview of clinical aspects of this disorder and closely related conditions, the molecular mechanisms underlying pathogenesis, and major genotype-phenotype correlations. ..
  5. Das B, Shu X, Day G, Han J, Krishna U, Falck J, et al. Control of intramolecular interactions between the pleckstrin homology and Dbl homology domains of Vav and Sos1 regulates Rac binding. J Biol Chem. 2000;275:15074-81 pubmed
    ..These results suggest the molecular mechanisms for activation of Vav and Sos1 require disruption of inhibitory intramolecular interactions involving the pleckstrin homology and Dbl homology domains. ..
  6. Fan P, Goff S. Abl interactor 1 binds to sos and inhibits epidermal growth factor- and v-Abl-induced activation of extracellular signal-regulated kinases. Mol Cell Biol. 2000;20:7591-601 pubmed
    ..Taken together, these findings suggest that overexpressed Abi proteins negatively regulate cell growth and transformation by specifically targeting the Erk pathway. ..
  7. McDonald C, Seldeen K, Deegan B, Farooq A. Structural basis of the differential binding of the SH3 domains of Grb2 adaptor to the guanine nucleotide exchange factor Sos1. Arch Biochem Biophys. 2008;479:52-62 pubmed publisher
    ..Taken together, our study provides structural basis of the differential binding of SH3 domains of Grb2 to Sos1 and a detailed thermodynamic profile of this key protein-protein interaction pertinent to cellular signaling and cancer. ..
  8. Pierre S, Bats A, Coumoul X. Understanding SOS (Son of Sevenless). Biochem Pharmacol. 2011;82:1049-56 pubmed publisher
    ..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...
  9. Swanson K, Winter J, Reis M, Bentires Alj M, Greulich H, Grewal R, et al. SOS1 mutations are rare in human malignancies: implications for Noonan Syndrome patients. Genes Chromosomes Cancer. 2008;47:253-9 pubmed
    ..Our findings suggest that SOS1 is not a significant human oncogene in most cancers. Furthermore, NS patients with SOS1 mutations may not be at increased risk of developing cancer. ..

More Information


  1. Innocenti M, Tenca P, Frittoli E, Faretta M, Tocchetti A, Di Fiore P, et al. Mechanisms through which Sos-1 coordinates the activation of Ras and Rac. J Cell Biol. 2002;156:125-36 pubmed
    ..Thus, the involvement of Sos-1 at two distinct and differentially regulated steps of the signaling cascade allows for coordinated activation of Ras and Rac and different duration of their signaling within the cell. ..
  2. Houtman J, Yamaguchi H, Barda Saad M, Braiman A, Bowden B, Appella E, et al. Oligomerization of signaling complexes by the multipoint binding of GRB2 to both LAT and SOS1. Nat Struct Mol Biol. 2006;13:798-805 pubmed
    ..These data suggest that multipoint binding of distal adaptor proteins mediates the formation of oligomeric signaling clusters vital for intracellular signaling. ..
  3. Roberts A, Araki T, Swanson K, Montgomery K, Schiripo T, Joshi V, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet. 2007;39:70-4 pubmed
    ..Our results identify SOS1 mutants as a major cause of Noonan syndrome, representing the first example of activating GEF mutations associated with human disease and providing new insights into RAS-GEF regulation. ..
  4. Hart T, Zhang Y, Gorry M, Hart P, Cooper M, Marazita M, et al. A mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1. Am J Hum Genet. 2002;70:943-54 pubmed
    ..functionally important proline-rich SH3 binding domains normally present in the carboxyl-terminal region of the SOS1 protein. The resultant protein chimera contains the wild-type SOS1 protein for the N-terminal amino acids 1-1083 fused ..
  5. Scita G, Tenca P, Areces L, Tocchetti A, Frittoli E, Giardina G, et al. An effector region in Eps8 is responsible for the activation of the Rac-specific GEF activity of Sos-1 and for the proper localization of the Rac-based actin-polymerizing machine. J Cell Biol. 2001;154:1031-44 pubmed
    ..In this complex, determinants of Eps8 are responsible for the proper localization of the Rac-activating machine to sites of actin remodeling. ..
  6. McDonald C, Seldeen K, Deegan B, Farooq A. SH3 domains of Grb2 adaptor bind to PXpsiPXR motifs within the Sos1 nucleotide exchange factor in a discriminate manner. Biochemistry. 2009;48:4074-85 pubmed publisher
    ..Taken together, this study furthers our understanding of the assembly of a key signaling complex central to cellular machinery. ..
  7. Nag A, Monine M, Faeder J, Goldstein B. Aggregation of membrane proteins by cytosolic cross-linkers: theory and simulation of the LAT-Grb2-SOS1 system. Biophys J. 2009;96:2604-23 pubmed publisher
    ..We discuss the model predictions in light of recent experiments on RBL-2H3 and Jurkat E6.1 cells and suggest that the gel phase has been observed in activated mast cells. ..
  8. Zheng J, Chen R, Corblan Garcia S, Cahill S, Bar Sagi D, Cowburn D. 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. J Biol Chem. 1997;272:30340-4 pubmed
  9. Hanna N, Parfait B, Talaat I, Vidaud M, Elsedfy H. SOS1: a new player in the Noonan-like/multiple giant cell lesion syndrome. Clin Genet. 2009;75:568-71 pubmed publisher
    ..Gain-of-function mutations in the SOS1 gene were recently described as the second major cause of NS. Here, we report for the first time the involvement of SOS1 gene in a family with the Noonan-like/multiple giant cell lesion phenotype. ..
  10. Denayer E, Devriendt K, de Ravel T, Van Buggenhout G, Smeets E, Francois I, et al. Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations. Genes Chromosomes Cancer. 2010;49:242-52 pubmed publisher
    ..One patient with a RAF1 mutation had a lesion suggestive for a giant cell tumor. This is the first report describing different tumor types in NS patients with germ line SOS1 mutations. ..
  11. Zenker M, Horn D, Wieczorek D, Allanson J, Pauli S, van der Burgt I, et al. SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. J Med Genet. 2007;44:651-6 pubmed
    ..Mutations of SOS1, the gene encoding a guanine nucleotide exchange factor for Ras, have been the most recent discoveries in patients with NS, but this gene has not been studied in patients with CFCS...
  12. Gureasko J, Kuchment O, Makino D, Sondermann H, Bar Sagi D, Kuriyan J. Role of the histone domain in the autoinhibition and activation of the Ras activator Son of Sevenless. Proc Natl Acad Sci U S A. 2010;107:3430-5 pubmed publisher
  13. Gureasko J, Galush W, Boykevisch S, Sondermann H, Bar Sagi D, Groves J, et al. Membrane-dependent signal integration by the Ras activator Son of sevenless. Nat Struct Mol Biol. 2008;15:452-61 pubmed publisher
  14. Ko J, Kim J, Kim G, Yoo H. PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet. 2008;53:999-1006 pubmed publisher
    ..The molecular defects of NS are genetically heterogeneous and involve several genes other than PTPN11 related to the RAS-MAPK pathway. ..
  15. Yadav K, Bar Sagi D. Allosteric gating of Son of sevenless activity by the histone domain. Proc Natl Acad Sci U S A. 2010;107:3436-40 pubmed publisher
    ..Thus, Sos-H plays a critical role in governing the catalytic output of Sos through the coupling of membrane recruitment to the release of autoinhibition. ..
  16. Pierre S, Bats A, Chevallier A, Bui L, Ambolet Camoit A, Garlatti M, et al. Induction of the Ras activator Son of Sevenless 1 by environmental pollutants mediates their effects on cellular proliferation. Biochem Pharmacol. 2011;81:304-13 pubmed publisher
    ..Remarkably, our studies also suggest that SOS1 induction leads to functional effects similar to those elicited by the well-characterized oncogenic Ras mutations. ..
  17. Qian X, Esteban L, Vass W, Upadhyaya C, Papageorge A, Yienger K, et al. The Sos1 and Sos2 Ras-specific exchange factors: differences in placental expression and signaling properties. EMBO J. 2000;19:642-54 pubmed
    ..We conclude that Sos1 participates in both short- and long-term signaling, while Sos2-dependent signals are predominantly short-term. ..
  18. Mettouchi A, Klein S, Guo W, Lopez Lago M, Lemichez E, Westwick J, et al. Integrin-specific activation of Rac controls progression through the G(1) phase of the cell cycle. Mol Cell. 2001;8:115-27 pubmed
    ..This process is mediated by SOS and PI-3K and requires coordinate upstream signals through Shc and FAK. These results indicate that Rac is a crucial mediator of the integrin-specific control of cell cycle in endothelial cells. ..
  19. Narumi Y, Aoki Y, Niihori T, Sakurai M, Cave H, Verloes A, et al. Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome. J Hum Genet. 2008;53:834-41 pubmed publisher
    ..These three patients exhibited ectodermal abnormalities, such as curly hair, sparse eyebrows, and dry skin, and two of them showed mental retardation. Our results suggest that patients with SOS1 mutations range from NS to CFC syndrome...
  20. Tidyman W, Rauen K. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev. 2009;19:230-6 pubmed publisher
    ..Here we review the clinical and underlying molecular basis for each of these syndromes...
  21. Longoni M, Moncini S, Cisternino M, Morella I, Ferraiuolo S, Russo S, et al. Noonan syndrome associated with both a new Jnk-activating familial SOS1 and a de novo RAF1 mutations. Am J Med Genet A. 2010;152A:2176-84 pubmed publisher
  22. Nyström A, Ekvall S, Berglund E, Bjorkqvist M, Braathen G, Duchen K, et al. Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders. J Med Genet. 2008;45:500-6 pubmed publisher
    ..CFC is distinguished from NS by the presence of ectodermal abnormalities and more severe mental retardation in addition to the NS phenotype. The genetic aetiology of CFC was recently assigned to four genes: BRAF, KRAS, MEK1 and MEK2...
  23. Nimnual A, Bar Sagi D. The two hats of SOS. Sci STKE. 2002;2002:pe36 pubmed
    ..Nimnual and Bar-Sagi discuss how these two activities of SOS can be regulated and how SOS may be recruited to different cellular locations through interactions with the adaptor proteins Grb2 and E3b1. ..
  24. Tartaglia M, Pennacchio L, Zhao C, Yadav K, Fodale V, Sarkozy A, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007;39:75-9 pubmed
    ..Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development. ..
  25. Zhao C, Du G, Skowronek K, Frohman M, Bar Sagi D. Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos. Nat Cell Biol. 2007;9:706-12 pubmed
    ..Our findings establish a crucial role for PLD2 in the coupling of extracellular signals to Sos-mediated Ras activation, and provide new insights into the spatial coordination of this activation event. ..
  26. Beneteau C, Cave H, Moncla A, Dorison N, Munnich A, Verloes A, et al. SOS1 and PTPN11 mutations in five cases of Noonan syndrome with multiple giant cell lesions. Eur J Hum Genet. 2009;17:1216-21 pubmed publisher
    ..The term cherubism should be used only when multiple giant cell lesions occur without any other clinical and molecular evidence of Noonan syndrome, with or without mutations of the SH3BP2 gene...
  27. Kinkl N, Hageman G, Sahel J, Hicks D. Fibroblast growth factor receptor (FGFR) and candidate signaling molecule distribution within rat and human retina. Mol Vis. 2002;8:149-60 pubmed
    ..Distinct differences in development, species, cell- and sub-cell type distribution were apparent, suggesting that specific FGFR/FGF ligands and transduction pathways may operate in different cells. ..
  28. Li K, Ann Thomas M, Haber R. Ulerythema ophryogenes, a rarely reported cutaneous manifestation of noonan syndrome: case report and review of the literature. J Cutan Med Surg. 2013;17:212-8 pubmed
    ..Further reports by dermatologists and medical geneticists documenting ulerythema ophryogenes and not just descriptions of sparse or absent eyebrows will help support this genotype-phenotype correlation. ..
  29. Tidyman W, Rauen K. Noonan, Costello and cardio-facio-cutaneous syndromes: dysregulation of the Ras-MAPK pathway. Expert Rev Mol Med. 2008;10:e37 pubmed publisher
    ..Here we review the clinical consequences of the known molecular lesions associated with Noonan syndrome, Costello syndrome and cardio-facio-cutaneous syndrome, and explore possible therapeutic modalities for treatment. ..
  30. McDonald C, Seldeen K, Deegan B, Bhat V, Farooq A. Assembly of the Sos1-Grb2-Gab1 ternary signaling complex is under allosteric control. Arch Biochem Biophys. 2010;494:216-25 pubmed publisher
  31. Quilliam L, Castro A, Rogers Graham K, Martin C, Der C, Bi C. M-Ras/R-Ras3, a transforming ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6. J Biol Chem. 1999;274:23850-7 pubmed
    ..Together, these findings suggest that while M-Ras is regulated by similar upstream stimuli to Ha-Ras, novel targets may be responsible for its effects on cellular transformation and differentiation. ..
  32. Timofeeva O, Zhang X, Ressom H, Varghese R, Kallakury B, Wang K, et al. Enhanced expression of SOS1 is detected in prostate cancer epithelial cells from African-American men. Int J Oncol. 2009;35:751-60 pubmed
  33. Saha M, Carriere A, Cheerathodi M, Zhang X, Lavoie G, Rush J, et al. RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation. Biochem J. 2012;447:159-66 pubmed publisher
    ..Together these data suggest that one mechanism whereby RSK negatively regulates MAPK activation is via site-specific SOS1 phosphorylation. ..
  34. Ferrero G, Picco G, Baldassarre G, Flex E, Isella C, Cantarella D, et al. Transcriptional hallmarks of Noonan syndrome and Noonan-like syndrome with loose anagen hair. Hum Mutat. 2012;33:703-9 pubmed publisher
  35. Burns M, Sun Q, Daniels R, Camper D, Kennedy J, Phan J, et al. Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange. Proc Natl Acad Sci U S A. 2014;111:3401-6 pubmed publisher
    ..These small molecules represent tools to study the acute activation of Ras and highlight a pocket on SOS that may be exploited to modulate Ras signaling. ..
  36. Kortum R, Sommers C, Alexander C, Pinski J, Li W, Grinberg A, et al. Targeted Sos1 deletion reveals its critical role in early T-cell development. Proc Natl Acad Sci U S A. 2011;108:12407-12 pubmed publisher
    ..These data reveal that Sos1 is uniquely positioned to affect signal transduction early in thymocyte development. ..
  37. Lioubin M, Myles G, Carlberg K, Bowtell D, Rohrschneider L. Shc, Grb2, Sos1, and a 150-kilodalton tyrosine-phosphorylated protein form complexes with Fms in hematopoietic cells. Mol Cell Biol. 1994;14:5682-91 pubmed
  38. Zaritsky A, Tseng Y, Rabadán M, Krishna S, Overholtzer M, Danuser G, et al. Diverse roles of guanine nucleotide exchange factors in regulating collective cell migration. J Cell Biol. 2017;216:1543-1556 pubmed publisher
    ..We conclude that for effective collective migration, the RHOA-GEFs ? RHOA/C ? actomyosin pathways must be optimally tuned to compromise between generation of motility forces and restriction of intercellular communication. ..
  39. Nishi M, Ryo A, Tsurutani N, Ohba K, Sawasaki T, Morishita R, et al. Requirement for microtubule integrity in the SOCS1-mediated intracellular dynamics of HIV-1 Gag. FEBS Lett. 2009;583:1243-50 pubmed publisher
    ..We thus propose that the microtubule network plays a role in SOCS1-mediated HIV-1 Gag transport and virus particle formation. ..
  40. Sacco E, Metalli D, Busti S, Fantinato S, D Urzo A, Mapelli V, et al. Catalytic competence of the Ras-GEF domain of hSos1 requires intra-REM domain interactions mediated by phenylalanine 577. FEBS Lett. 2006;580:6322-8 pubmed
    ..We show that an intra-REM domain interaction, mediated by phenylalanine 577, is required to allow interaction of the REM domain with the catalytic core, constraining it in the active conformation. ..
  41. Goicoechea S, Arneman D, Disanza A, Garcia Mata R, Scita G, Otey C. Palladin binds to Eps8 and enhances the formation of dorsal ruffles and podosomes in vascular smooth muscle cells. J Cell Sci. 2006;119:3316-24 pubmed
  42. Miura K, Miyazawa S, Furuta S, Mitsushita J, Kamijo K, Ishida H, et al. The Sos1-Rac1 signaling. Possible involvement of a vacuolar H(+)-ATPase E subunit. J Biol Chem. 2001;276:46276-83 pubmed
    ..Thus, the data indicate that V-ATPase E may participate in the regulation of the mSos1-dependent Rac1 signaling pathway involved in growth factor receptor-mediated cell growth control. ..
  43. Zenker M. Genetic and pathogenetic aspects of Noonan syndrome and related disorders. Horm Res. 2009;72 Suppl 2:57-63 pubmed publisher
    ..It discusses the relationship between a group of developmental disorders and oncogenes. Potential future treatment prospects are based on the possibility of inhibiting RAS-MAPK signaling by pharmaceuticals...
  44. DeAngelo S, Murphy J, Claman L, Kalmar J, Leblebicioglu B. Hereditary gingival fibromatosis--a review. Compend Contin Educ Dent. 2007;28:138-43; quiz 144, 152 pubmed
    ..This article reviews differential diagnosis, etiology, complications, and treatment of HGF. ..
  45. Ozaki K, Miyazaki S, Tanimura S, Kohno M. Efficient suppression of FGF-2-induced ERK activation by the cooperative interaction among mammalian Sprouty isoforms. J Cell Sci. 2005;118:5861-71 pubmed
    ..The cooperative interactions observed among Sprouty isoforms could represent an advanced system that functions to regulate strictly the activation state of the RTK/ERK pathway in mammalian cells...
  46. Lepri F, De Luca A, Stella L, Rossi C, Baldassarre G, Pantaleoni F, et al. SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. Hum Mutat. 2011;32:760-72 pubmed publisher
  47. Dangi S, Shapiro P. Cdc2-mediated inhibition of epidermal growth factor activation of the extracellular signal-regulated kinase pathway during mitosis. J Biol Chem. 2005;280:24524-31 pubmed
    ..These data suggest that Cdc2 inhibits growth factor receptor-mediated ERK activation during mitosis by primarily targeting signaling proteins that are upstream of MEK1. ..
  48. Endou M, Mizuno M, Nagata T, Tsukada K, Nakahara N, Tsuno T, et al. Growth inhibition of human pancreatic cancer cells by human interferon-beta gene combined with gemcitabine. Int J Mol Med. 2005;15:277-83 pubmed
    ..These results suggest that this combination therapy can induce strong anti-tumor activity against human pancreatic cancer cells through the regulation of the Ras-related signal pathway. ..
  49. Barroso I, Luan J, Middelberg R, Harding A, Franks P, Jakes R, et al. Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action. PLoS Biol. 2003;1:E20 pubmed
    ..The absence of large single-gene effects and the detection of multiple small effects accentuate the need for the study of larger populations in order to reliably identify the size of effect we now expect for complex diseases...
  50. De Corte V, Bruyneel E, Boucherie C, Mareel M, Vandekerckhove J, Gettemans J. Gelsolin-induced epithelial cell invasion is dependent on Ras-Rac signaling. EMBO J. 2002;21:6781-90 pubmed
    ..These findings establish a connection between gelsolin and the Ras oncogenic signaling pathway. ..
  51. Hamada A, Hibino T, Nakamura T, Takabe T. Na+/H+ antiporter from Synechocystis species PCC 6803, homologous to SOS1, contains an aspartic residue and long C-terminal tail important for the carrier activity. Plant Physiol. 2001;125:437-46 pubmed
    ..Thus, it appeared that the SynNhaP would provide a model system for the study of structural and functional properties of eucaryotic Na(+)/H(+) antiporters. ..
  52. Tong X, Hussain N, de Heuvel E, Kurakin A, Abi Jaoude E, Quinn C, et al. The endocytic protein intersectin is a major binding partner for the Ras exchange factor mSos1 in rat brain. EMBO J. 2000;19:1263-71 pubmed
    ..These results suggest that intersectin functions in cell signaling in addition to its role in endocytosis and may link these cellular processes. ..
  53. Leprince C, Romero F, Cussac D, Vayssiere B, Berger R, Tavitian A, et al. A new member of the amphiphysin family connecting endocytosis and signal transduction pathways. J Biol Chem. 1997;272:15101-5 pubmed
    ..This hypothesis is strengthened by the ability of BRAMP2 to interact with the p21(ras) exchange factor SOS, in vitro, as a possible point of interconnection between the endocytic and signaling pathways. ..