son of sevenless proteins


Summary: A class of RAS GUANINE NUCLEOTIDE EXCHANGE FACTORS that are genetically related to the Son of Sevenless gene from DROSOPHILA. Sevenless refers to genetic mutations in DROSOPHILA that cause loss of the R7 photoreceptor which is required to see UV light.

Top Publications

  1. Upadhyay D, Correa Meyer E, Sznajder J, Kamp D. FGF-10 prevents mechanical stretch-induced alveolar epithelial cell DNA damage via MAPK activation. Am J Physiol Lung Cell Mol Physiol. 2003;284:L350-9 pubmed
    ..We conclude that cyclic stretch causes AEC DNA damage and that FGF-10 attenuates these effects by mechanisms involving MAPK activation via the Grb2-SOS/Ras/RAF-1/ERK1/2 pathway. ..
  2. Morrison H, Sperka T, Manent J, Giovannini M, Ponta H, Herrlich P. Merlin/neurofibromatosis type 2 suppresses growth by inhibiting the activation of Ras and Rac. Cancer Res. 2007;67:520-7 pubmed
    ..We propose that the interference of merlin with Ras- and Rac-dependent signal transfer represents part of the tumor-suppressive action of merlin. ..
  3. Yang S, Van Aelst L, Bar Sagi D. Differential interactions of human Sos1 and Sos2 with Grb2. J Biol Chem. 1995;270:18212-5 pubmed
    ..The region conferring this higher binding affinity has been mapped to residues 1126-1242 of the hSos2 COOH-terminal domain. These results suggest that Sos1 and Sos2 may differentially contribute to receptor-mediated Ras activation. ..
  4. 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. ..
  5. Margarit S, Sondermann H, Hall B, Nagar B, Hoelz A, Pirruccello M, et al. Structural evidence for feedback activation by Ras.GTP of the Ras-specific nucleotide exchange factor SOS. Cell. 2003;112:685-95 pubmed
    ..These results demonstrate the existence of a positive feedback mechanism for the spatial and temporal regulation of Ras. ..
  6. Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, et al. Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature. 1993;363:85-8 pubmed
    ..Moreover, a synthetic 10-amino-acid peptide containing the sequence PPVPPR specifically blocks the interaction. These results indicate that the Grb2/hSos1 complex couples activated EGF receptor to Ras signalling. ..
  7. Chardin P, Camonis J, Gale N, Van Aelst L, Schlessinger J, Wigler M, et al. Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science. 1993;260:1338-43 pubmed
    ..These results suggest that the coupling of receptor tyrosine kinases to Ras signaling is mediated by a molecular complex consisting of GRB2 and hSos1. ..
  8. Cullen P, Lockyer P. Integration of calcium and Ras signalling. Nat Rev Mol Cell Biol. 2002;3:339-48 pubmed
    ..Here, we focus on examining the link between calcium and Ras signalling and, in particular, we speculate as to how the complexity of calcium signalling could regulate Ras activity. ..
  9. Orian Rousseau V, Morrison H, Matzke A, Kastilan T, Pace G, Herrlich P, et al. Hepatocyte growth factor-induced Ras activation requires ERM proteins linked to both CD44v6 and F-actin. Mol Biol Cell. 2007;18:76-83 pubmed
    ..So far the cytoskeleton has mainly been identified as a "responder" to signal transduction. Here, we show now that F-actin acts as an "inducer" that actively organizes the signaling cascade. ..

More Information


  1. Sondermann H, Soisson S, Boykevisch S, Yang S, Bar Sagi D, Kuriyan J. Structural analysis of autoinhibition in the Ras activator Son of sevenless. Cell. 2004;119:393-405 pubmed
    ..The action of the DH-PH unit gates a reciprocal interaction between Ras and SOS, in which Ras converts SOS from low to high activity forms as Ras*GDP is converted to Ras*GTP by SOS. ..
  2. Egan S, Giddings B, Brooks M, Buday L, Sizeland A, Weinberg R. Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature. 1993;363:45-51 pubmed
    ..Ectopic expression of Drosophila Sos stimulates morphological transformation of rodent fibroblasts. These data define a pathway by which tyrosine kinases act through Ras to control cell growth and differentiation. ..
  3. Rozakis Adcock M, Fernley R, Wade J, Pawson T, Bowtell D. The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1. Nature. 1993;363:83-5 pubmed
    ..EGF stimulation induces binding of the Grb2-mSos1 complex to the autophosphorylated EGF receptor, and mSos1 phosphorylation. Grb2 therefore appears to link tyrosine kinases to a Ras-GNRP in mammalian cells. ..
  4. Skolnik E, Batzer A, Li N, Lee C, Lowenstein E, Mohammadi M, et al. The function of GRB2 in linking the insulin receptor to Ras signaling pathways. Science. 1993;260:1953-5 pubmed
  5. Smit L, van der Horst G, Borst J. Sos, Vav, and C3G participate in B cell receptor-induced signaling pathways and differentially associate with Shc-Grb2, Crk, and Crk-L adaptors. J Biol Chem. 1996;271:8564-9 pubmed
    ..Since Cbl binds to Grb2, Crk, as well as Crk-L, we hypothesize that Cbl may affect the function of all three exchangers. ..
  6. Illario M, Amideo V, Casamassima A, Andreucci M, Di Matola T, Miele C, et al. Integrin-dependent cell growth and survival are mediated by different signals in thyroid cells. J Clin Endocrinol Metab. 2003;88:260-9 pubmed
    ..These results demonstrate that in thyroid cells adhesion to FN regulates proliferation through the p21Ras/MAPK signal pathway, whereas integrin-mediated cell survival is mediated by PI3K. ..
  7. Park R, Kim D, Kim M, So H, Chung H, Kwon K, et al. Association of Shc, Cbl, Grb2, and Sos following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin in primary rat hepatocytes. Biochem Biophys Res Commun. 1998;253:577-81 pubmed
    ..Furthermore, tyrosine phosphorylation of Cbl may not be critical for interaction of the protein with Grb2 and Shc in the TCDD signaling pathway in primary rat hepatocytes. ..
  8. Christensen S, Triplet M, Rhodes C, Iwig J, Tu H, Stamou D, et al. Monitoring the Waiting Time Sequence of Single Ras GTPase Activation Events Using Liposome Functionalized Zero-Mode Waveguides. Nano Lett. 2016;16:2890-5 pubmed publisher
    ..Liposome functionalized ZMWs allow for studies of nucleotide exchange reactions at single GTPase resolution, providing a platform to gauge the mechanisms of these processes. ..
  9. Moeller S, Head E, Sheaff R. p27Kip1 inhibition of GRB2-SOS formation can regulate Ras activation. Mol Cell Biol. 2003;23:3735-52 pubmed
    ..Thus, p27 downregulation may compromise control of Ras, one of the most common oncogenic events in human cancer. ..
  10. Maurer T, Garrenton L, Oh A, Pitts K, Anderson D, Skelton N, et al. Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc Natl Acad Sci U S A. 2012;109:5299-304 pubmed publisher
    ..The discovery of a small-molecule binding pocket on Ras with functional significance provides a new direction in the search of therapeutically effective inhibitors of the Ras oncoprotein. ..
  11. Curto M, Frankel P, Carrero A, Foster D. Novel recruitment of Shc, Grb2, and Sos by fibroblast growth factor receptor-1 in v-Src-transformed cells. Biochem Biophys Res Commun. 1998;243:555-60 pubmed
    ..These data suggest a mechanism for Ras activation by v-Src involving phosphorylation of novel tyrosine(s) on FGFR-1. ..
  12. Olivier J, Raabe T, Henkemeyer M, Dickson B, Mbamalu G, Margolis B, et al. A Drosophila SH2-SH3 adaptor protein implicated in coupling the sevenless tyrosine kinase to an activator of Ras guanine nucleotide exchange, Sos. Cell. 1993;73:179-91 pubmed
    ..The conservation of these signaling proteins during evolution indicates that this is a general mechanism for linking tyrosine kinases to Ras. ..
  13. Rebecchi M, Scarlata S. Pleckstrin homology domains: a common fold with diverse functions. Annu Rev Biophys Biomol Struct. 1998;27:503-28 pubmed
    ..Despite minimal sequence homology, the three-dimensional structures are remarkably conserved. This review gives an overview of the PH domain architecture and examines the best-studied examples in an attempt to understand their function. ..
  14. Bonfini L, Karlovich C, Dasgupta C, Banerjee U. The Son of sevenless gene product: a putative activator of Ras. Science. 1992;255:603-6 pubmed
    ..These results imply a role for the ras pathway in Drosophila neuronal development. ..
  15. Arai J, Li S, Feig L. Sos2 is dispensable for NMDA-induced Erk activation and LTP induction. Neurosci Lett. 2009;455:22-5 pubmed publisher
    ..These results imply that Sos1 is the major regulator of these well-known neuronal Sos functions and suggest that a novel function for Sos2 in neurons remains to be determined. ..
  16. Bertorello A, Zhu J. SIK1/SOS2 networks: decoding sodium signals via calcium-responsive protein kinase pathways. Pflugers Arch. 2009;458:613-9 pubmed publisher
    ..Activation of these networks prevents abnormal increases in intracellular sodium concentration. ..
  17. Buday L, Downward J. Many faces of Ras activation. Biochim Biophys Acta. 2008;1786:178-87 pubmed publisher
    ..Although all of them are able to activate Ras, their structure, tissue expression and regulation are significantly diverse. In this review we will summarize the various mechanisms by which these exchange factors activate Ras. ..
  18. den Hertog J, Tracy S, Hunter T. Phosphorylation of receptor protein-tyrosine phosphatase alpha on Tyr789, a binding site for the SH3-SH2-SH3 adaptor protein GRB-2 in vivo. EMBO J. 1994;13:3020-32 pubmed
    ..Our results suggest a role for RPTP alpha in attenuation of GRB2-mediated signaling. ..
  19. Karna E, Miltyk W, Pałka J. Butyrate-induced collagen biosynthesis in cultured fibroblasts is independent on alpha2beta1 integrin signalling and undergoes through IGF-I receptor cascade. Mol Cell Biochem. 2006;286:147-52 pubmed
    ..The data suggests that butyrate-dependent stimulation of collagen biosynthesis in cultured human skin fibroblasts undergoes through IGF-IR signaling. ..
  20. Sondermann H, Nagar B, Bar Sagi D, Kuriyan J. Computational docking and solution x-ray scattering predict a membrane-interacting role for the histone domain of the Ras activator son of sevenless. Proc Natl Acad Sci U S A. 2005;102:16632-7 pubmed
    ..The orientation and position of the histone domain in the SOS model implicates it as a potential mediator of membrane-dependent activation signals. ..
  21. Aoki K, Nakamura T, Fujikawa K, Matsuda M. Local phosphatidylinositol 3,4,5-trisphosphate accumulation recruits Vav2 and Vav3 to activate Rac1/Cdc42 and initiate neurite outgrowth in nerve growth factor-stimulated PC12 cells. Mol Biol Cell. 2005;16:2207-17 pubmed
    ..These observations demonstrated for the first time that Vav2 and Vav3 are essential constituents of the positive feedback loop that is comprised of PI3-kinase and Rac1/Cdc42 and cycles locally with morphological changes. ..
  22. Chie L, Friedman F, Duncan T, Chen J, Chung D, Pincus M. Loop domain peptides from the SOS ras-guanine nucleotide exchange protein, identified from molecular dynamics calculations, strongly inhibit ras signaling. Protein J. 2004;23:229-34 pubmed
    ..These results suggest that SOS contains domains, including the three loop domains, that are important for ras signaling and that several of these domains can activate different pathways specific to oncogenic or wild-type ras-p21. ..
  23. Sondermann H, Soisson S, Bar Sagi D, Kuriyan J. Tandem histone folds in the structure of the N-terminal segment of the ras activator Son of Sevenless. Structure. 2003;11:1583-93 pubmed
    ..Residues that form a contiguous patch on the surface of the histone domain of Sos are conserved from C. elegans to humans, suggesting a potential role for this domain in protein-protein interactions. ..
  24. Fath I, Apiou F, Schweighoffer F, Chevallier Multon M, Ciora T, Dutrillaux B, et al. Identification of two human homologues to Drosophila SOS (son of sevenless) localized on two different chromosomes. Nucleic Acids Res. 1993;21:4398 pubmed
  25. Kardinal C, Konkol B, Lin H, Eulitz M, Schmidt E, Estrov Z, et al. Chronic myelogenous leukemia blast cell proliferation is inhibited by peptides that disrupt Grb2-SoS complexes. Blood. 2001;98:1773-81 pubmed
    ..These results show that, in addition to the direct targeting of Bcr-Abl, selective inhibition of Grb2 protein complexes may be a therapeutic option for a significant number of CML patients. ..
  26. Feller S, Tuchscherer G, Voss J. High affinity molecules disrupting GRB2 protein complexes as a therapeutic strategy for chronic myelogenous leukaemia. Leuk Lymphoma. 2003;44:411-27 pubmed
    ..Since Grb2 is a known signal transducer for several major human oncogenes, this approach may have applications for a wider range of human cancers. ..
  27. Lu S, Jang H, Zhang J, Nussinov R. Inhibitors of Ras-SOS Interactions. ChemMedChem. 2016;11:814-21 pubmed publisher
    ..A repertoire of classified cancer, cell/tissue, and pathway/protein combinations would be beneficial toward this goal. ..
  28. Kumkhaek C, Aerbajinai W, Liu W, Zhu J, Uchida N, Kurlander R, et al. MASL1 induces erythroid differentiation in human erythropoietin-dependent CD34+ cells through the Raf/MEK/ERK pathway. Blood. 2013;121:3216-27 pubmed publisher
    ..Importantly, we also demonstrated that MASL1 interacts physically with Raf1. Taken together, our data provide novel insights into MASL1 regulation of erythropoiesis through the Raf/MEK/ERK pathway. ..
  29. Chauhan D, Kharbanda S, Ogata A, Urashima M, Frank D, Malik N, et al. Oncostatin M induces association of Grb2 with Janus kinase JAK2 in multiple myeloma cells. J Exp Med. 1995;182:1801-6 pubmed
    ..The SH2 domain of Grb2 is directly associated with tyrosine-phosphorylated JAK2. Furthermore, the presence of Sos in the JAK2-Grb2 complex suggests a role for Ras in OSM-transduced signaling. ..
  30. Liu A, Lo R, Lee M, Wang Y, Yeung W, Ho M, et al. Galpha16 activates Ras by forming a complex with tetratricopeptide repeat 1 (TPR1) and Son of Sevenless (SOS). Cell Signal. 2010;22:1448-58 pubmed publisher
    ..Collectively, our results suggest that Galpha16 regulates multiple signaling pathways by activating Ras through its association with TPR1, but TPR1 is not required for Galpha16 to stimulate phospholipase Cbeta. ..
  31. Kanai M, Göke M, Tsunekawa S, Podolsky D. Signal transduction pathway of human fibroblast growth factor receptor 3. Identification of a novel 66-kDa phosphoprotein. J Biol Chem. 1997;272:6621-8 pubmed
    ..pp66.GRB2.Sos; these two complexes may alternatively link FGFG3 to mitogen-activated protein kinase. Finally, activated FGFR3 was also found to result in phosphorylation of phospholipase C-gamma but reduced phosphorylation of c-Src. ..
  32. Buday L, Egan S, Rodriguez Viciana P, Cantrell D, Downward J. A complex of Grb2 adaptor protein, Sos exchange factor, and a 36-kDa membrane-bound tyrosine phosphoprotein is implicated in ras activation in T cells. J Biol Chem. 1994;269:9019-23 pubmed
    ..CD3 complex might be controlled, at least in part, by mechanisms similar to those found in fibroblasts, involving in this case formation of a complex of Grb2, Sos, and a membrane-bound tyrosine phosphoprotein of molecular mass 36-kDa. ..
  33. 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. ..
  34. de Hoog C, Koehler J, Goldstein M, Taylor P, Figeys D, Moran M. Ras binding triggers ubiquitination of the Ras exchange factor Ras-GRF2. Mol Cell Biol. 2001;21:2107-17 pubmed
    ..We conclude that conformational changes induced by GTPase binding expose the DB and thereby target GRF2 for destruction. ..
  35. Hishida T, Han Y, Shibata T, Kubota Y, Ishino Y, Iwasaki H, et al. Role of the Escherichia coli RecQ DNA helicase in SOS signaling and genome stabilization at stalled replication forks. Genes Dev. 2004;18:1886-97 pubmed
  36. Gotoh T, Hattori S, Nakamura S, Kitayama H, Noda M, Takai Y, et al. Identification of Rap1 as a target for the Crk SH3 domain-binding guanine nucleotide-releasing factor C3G. Mol Cell Biol. 1995;15:6746-53 pubmed
    ..Furthermore, expression of C3G with a membrane localization signal in a v-Ki-ras transformant, DT, induced a reversion of the cells to the flat form, possibly through the activation of endogenous Rap1. ..
  37. Yulug I, Egan S, Pollock P, Fisher E. A homologue of the Drosophila Son of sevenless gene maps to mouse chromosome 17. Genomics. 1993;18:733-4 pubmed
  38. Wang D, Li Z, Schoen S, Messing E, Wu G. A novel MET-interacting protein shares high sequence similarity with RanBPM, but fails to stimulate MET-induced Ras/Erk signaling. Biochem Biophys Res Commun. 2004;313:320-6 pubmed
  39. Li S, Kim M, Hu Y, Jalali S, Schlaepfer D, Hunter T, et al. Fluid shear stress activation of focal adhesion kinase. Linking to mitogen-activated protein kinases. J Biol Chem. 1997;272:30455-62 pubmed
    ..These results demonstrate that FAK signaling is critical in the shear stress-induced dual activation of ERK and JNK. ..
  40. Saleem A, Kharbanda S, Yuan Z, Kufe D. Monocyte colony-stimulating factor stimulates binding of phosphatidylinositol 3-kinase to Grb2.Sos complexes in human monocytes. J Biol Chem. 1995;270:10380-3 pubmed
    ..Since Sos binds to the SH3 domains of Grb2 and thereby associates with Ras at the cell membrane, formation of the PI 3-kinase.Grb2.Sos complex provides a potential mechanism for growth factor-induced interactions of PI 3-kinase and Ras. ..
  41. Sibilia M, Fleischmann A, Behrens A, Stingl L, Carroll J, Watt F, et al. The EGF receptor provides an essential survival signal for SOS-dependent skin tumor development. Cell. 2000;102:211-20 pubmed
    ..Therefore, EGFR functions as a survival factor in oncogenic transformation and provides a valuable target for therapeutic intervention in a broader range of tumors than anticipated. ..
  42. Yam J, Jin D, So C, Chan L. Identification and characterization of EBP, a novel EEN binding protein that inhibits Ras signaling and is recruited into the nucleus by the MLL-EEN fusion protein. Blood. 2004;103:1445-53 pubmed
    ..Taken together, our findings suggest a new mechanism for MLL-EEN-mediated leukemogenesis in which MLL-EEN interferes with the Ras-suppressing activities of EBP through direct interaction. ..
  43. Kurada B, Li L, Mulherkar N, Subramanian M, Prasad K, Prabhakar B. MADD, a splice variant of IG20, is indispensable for MAPK activation and protection against apoptosis upon tumor necrosis factor-alpha treatment. J Biol Chem. 2009;284:13533-41 pubmed publisher
  44. Wasiak S, Quinn C, Ritter B, de Heuvel E, Baranes D, Plomann M, et al. The Ras/Rac guanine nucleotide exchange factor mammalian Son-of-sevenless interacts with PACSIN 1/syndapin I, a regulator of endocytosis and the actin cytoskeleton. J Biol Chem. 2001;276:26622-8 pubmed
    ..These data suggest that PACSINs may function with mSos1 in regulation of actin dynamics. ..
  45. Tumurkhuu M, Saitoh M, Sato A, Takahashi K, Mimaki M, Takita J, et al. Comprehensive genetic analysis of overlapping syndromes of RAS/RAF/MEK/ERK pathway. Pediatr Int. 2010;52:557-62 pubmed publisher
    ..A case mimicking CS with SOS1 T158A substitution, which has not been reported previously in CS, revealed the complex relationship between the genotype and phenotype of overlapping syndromes of the RAS/RAF/MEK/ERK pathway. ..
  46. Shi G, Jin L, Andres D. Src-dependent TrkA transactivation is required for pituitary adenylate cyclase-activating polypeptide 38-mediated Rit activation and neuronal differentiation. Mol Biol Cell. 2010;21:1597-608 pubmed publisher
    ..Together, these observations expand upon the nature of PACR1-mediated transactivation and identify TrkA-Rit signaling as a key contributor to PACAP-dependent neuronal differentiation. ..
  47. Sienkiewicz P, Bielawski K, Bielawska A, Pałka J. Amidine analogue of chlorambucil is a stronger inhibitor of protein and DNA synthesis in breast cancer MCF-7 cells than is the parent drug. Eur J Pharmacol. 2004;492:95-101 pubmed
    ..These data suggest that the amidine analogue of chlorambucil is a stronger inhibitor of protein and DNA synthesis in MCF-7 cells than is the parent drug. ..
  48. Deshpande P, Cavanagh M, Le Saux S, Singh K, Weyand C, Goronzy J. IL-7- and IL-15-mediated TCR sensitization enables T cell responses to self-antigens. J Immunol. 2013;190:1416-23 pubmed publisher
    ..We propose that HCs, possibly induced by lymphopenia, decrease the signaling threshold for TCR activation and are thereby partly responsible for autoimmunity in RA. ..
  49. Kwan D, Yung L, Ye R, Wong Y. Activation of Ras-dependent signaling pathways by G(14) -coupled receptors requires the adaptor protein TPR1. J Cell Biochem. 2012;113:3486-97 pubmed publisher
    ..Our results suggest that TPR1 is required for G?(14) to stimulate Ras-dependent signaling pathways, but not for the propagation of signals along Ras-independent pathways. ..
  50. Limpert A, Karlo J, Landreth G. Nerve growth factor stimulates the concentration of TrkA within lipid rafts and extracellular signal-regulated kinase activation through c-Cbl-associated protein. Mol Cell Biol. 2007;27:5686-98 pubmed
    ..These data provide a mechanism for the lipid raft localization of TrkA and establish the importance of the CAP adaptor protein for NGF activation of the ERKs and neuronal differentiation. ..
  51. Khanday F, Santhanam L, Kasuno K, Yamamori T, Naqvi A, Dericco J, et al. Sos-mediated activation of rac1 by p66shc. J Cell Biol. 2006;172:817-22 pubmed
    ..This relationship between p66shc, grb2, and sos1 provides a novel mechanism for the activation of rac1. ..
  52. Chakraborty A, Das J, Zikherman J, Yang M, Govern C, Ho M, et al. Molecular origin and functional consequences of digital signaling and hysteresis during Ras activation in lymphocytes. Sci Signal. 2009;2:pt2 pubmed publisher
  53. Scholler J, Perez Villar J, O Day K, Kanner S. Engagement of the T lymphocyte antigen receptor regulates association of son-of-sevenless homologues with the SH3 domain of phospholipase Cgamma1. Eur J Immunol. 2000;30:2378-87 pubmed
    ..Together, the data suggest a mechanism for the son-of-sevenless and PLCgamma1 signal transducing enzymes in recruitment to protein complexes with potentially differential signaling consequences in T lymphocytes. ..