Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1995 Jan;15(1):379–388. doi: 10.1128/mcb.15.1.379

A dominant-negative mutant of mSOS1 inhibits insulin-induced Ras activation and reveals Ras-dependent and -independent insulin signaling pathways.

M Sakaue 1, D Bowtell 1, M Kasuga 1
PMCID: PMC231974  PMID: 7799946

Abstract

The role of the Grb2-SOS complex in insulin signal transduction was investigated with a deletion mutant of mSOS1 that lacks the guanine nucleotide exchange domain of the wild-type protein. Cells over-expressing either wild-type (CHO-IR/SOS cells) or mutant (CHO-IR/delta SOS cells) mSOS1 were established by transfection of Chinese hamster ovary cells that express human insulin receptors (CHO-IR cells) with the appropriate expression plasmid. The mutant mSOS1 protein did not contain the guanine nucleotide exchange activity in vitro and associated with Grb2 both in vivo and in vitro. In both CHO-IR and CHO-IR/SOS cells, insulin rapidly stimulated the formation of GTP-bound Ras and the phosphorylation of mitogen-activated protein (MAP) kinase; both these effects of insulin were markedly inhibited in CHO-IR/delta SOS cells. Insulin-induced glycogen synthase and 70-kDa S6 kinase activities were not affected by expression of either wild-type or mutant mSOS1. These results show that the mutant mSOS1 acts in a dominant-negative manner and suggest that the Grb2-SOS complex mediates, at least in part, insulin-induced activation of Ras in intact cells. The data also indicate that Ras activation is not required for insulin-induced stimulation of glycogen synthase and 70-kDa S6 kinase.

Full Text

The Full Text of this article is available as a PDF (485.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alcorta D. A., Crews C. M., Sweet L. J., Bankston L., Jones S. W., Erikson R. L. Sequence and expression of chicken and mouse rsk: homologs of Xenopus laevis ribosomal S6 kinase. Mol Cell Biol. 1989 Sep;9(9):3850–3859. doi: 10.1128/mcb.9.9.3850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ando A., Momomura K., Tobe K., Yamamoto-Honda R., Sakura H., Tamori Y., Kaburagi Y., Koshio O., Akanuma Y., Yazaki Y. Enhanced insulin-induced mitogenesis and mitogen-activated protein kinase activities in mutant insulin receptors with substitution of two COOH-terminal tyrosine autophosphorylation sites by phenylalanine. J Biol Chem. 1992 Jun 25;267(18):12788–12796. [PubMed] [Google Scholar]
  3. Ando A., Yonezawa K., Gout I., Nakata T., Ueda H., Hara K., Kitamura Y., Noda Y., Takenawa T., Hirokawa N. A complex of GRB2-dynamin binds to tyrosine-phosphorylated insulin receptor substrate-1 after insulin treatment. EMBO J. 1994 Jul 1;13(13):3033–3038. doi: 10.1002/j.1460-2075.1994.tb06602.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Backer J. M., Myers M. G., Jr, Shoelson S. E., Chin D. J., Sun X. J., Miralpeix M., Hu P., Margolis B., Skolnik E. Y., Schlessinger J. Phosphatidylinositol 3'-kinase is activated by association with IRS-1 during insulin stimulation. EMBO J. 1992 Sep;11(9):3469–3479. doi: 10.1002/j.1460-2075.1992.tb05426.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ballou L. M., Luther H., Thomas G. MAP2 kinase and 70K S6 kinase lie on distinct signalling pathways. Nature. 1991 Jan 24;349(6307):348–350. doi: 10.1038/349348a0. [DOI] [PubMed] [Google Scholar]
  6. Baltensperger K., Kozma L. M., Cherniack A. D., Klarlund J. K., Chawla A., Banerjee U., Czech M. P. Binding of the Ras activator son of sevenless to insulin receptor substrate-1 signaling complexes. Science. 1993 Jun 25;260(5116):1950–1952. doi: 10.1126/science.8391166. [DOI] [PubMed] [Google Scholar]
  7. Banerjee P., Ahmad M. F., Grove J. R., Kozlosky C., Price D. J., Avruch J. Molecular structure of a major insulin/mitogen-activated 70-kDa S6 protein kinase. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8550–8554. doi: 10.1073/pnas.87.21.8550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Blenis J., Erikson R. L. Phosphorylation of the ribosomal protein S6 is elevated in cells transformed by a variety of tumor viruses. J Virol. 1984 Jun;50(3):966–969. doi: 10.1128/jvi.50.3.966-969.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bowtell D., Fu P., Simon M., Senior P. Identification of murine homologues of the Drosophila son of sevenless gene: potential activators of ras. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6511–6515. doi: 10.1073/pnas.89.14.6511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Buday L., Downward J. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell. 1993 May 7;73(3):611–620. doi: 10.1016/0092-8674(93)90146-h. [DOI] [PubMed] [Google Scholar]
  11. Burgering B. M., Medema R. H., Maassen J. A., van de Wetering M. L., van der Eb A. J., McCormick F., Bos J. L. Insulin stimulation of gene expression mediated by p21ras activation. EMBO J. 1991 May;10(5):1103–1109. doi: 10.1002/j.1460-2075.1991.tb08050.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Burgering B. M., de Vries-Smits A. M., Medema R. H., van Weeren P. C., Tertoolen L. G., Bos J. L. Epidermal growth factor induces phosphorylation of extracellular signal-regulated kinase 2 via multiple pathways. Mol Cell Biol. 1993 Dec;13(12):7248–7256. doi: 10.1128/mcb.13.12.7248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chan C. P., Bowen-Pope D. F., Ross R., Krebs E. G. Regulation of glycogen synthase activity by growth factors. Relationship between synthase activation and receptor occupancy. J Biol Chem. 1987 Jan 5;262(1):276–281. [PubMed] [Google Scholar]
  14. Cheatham B., Vlahos C. J., Cheatham L., Wang L., Blenis J., Kahn C. R. Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol Cell Biol. 1994 Jul;14(7):4902–4911. doi: 10.1128/mcb.14.7.4902. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Chung J., Grammer T. C., Lemon K. P., Kazlauskas A., Blenis J. PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase. Nature. 1994 Jul 7;370(6484):71–75. doi: 10.1038/370071a0. [DOI] [PubMed] [Google Scholar]
  16. Chung J., Kuo C. J., Crabtree G. R., Blenis J. Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell. 1992 Jun 26;69(7):1227–1236. doi: 10.1016/0092-8674(92)90643-q. [DOI] [PubMed] [Google Scholar]
  17. Clark S. G., Stern M. J., Horvitz H. R. C. elegans cell-signalling gene sem-5 encodes a protein with SH2 and SH3 domains. Nature. 1992 Mar 26;356(6367):340–344. doi: 10.1038/356340a0. [DOI] [PubMed] [Google Scholar]
  18. Dent P., Lavoinne A., Nakielny S., Caudwell F. B., Watt P., Cohen P. The molecular mechanism by which insulin stimulates glycogen synthesis in mammalian skeletal muscle. Nature. 1990 Nov 22;348(6299):302–308. doi: 10.1038/348302a0. [DOI] [PubMed] [Google Scholar]
  19. Egan S. E., Giddings B. W., Brooks M. W., Buday L., Sizeland A. M., Weinberg R. A. Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature. 1993 May 6;363(6424):45–51. doi: 10.1038/363045a0. [DOI] [PubMed] [Google Scholar]
  20. Embi N., Rylatt D. B., Cohen P. Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J Biochem. 1980 Jun;107(2):519–527. [PubMed] [Google Scholar]
  21. Endemann G., Yonezawa K., Roth R. A. Phosphatidylinositol kinase or an associated protein is a substrate for the insulin receptor tyrosine kinase. J Biol Chem. 1990 Jan 5;265(1):396–400. [PubMed] [Google Scholar]
  22. Erikson R. L. Structure, expression, and regulation of protein kinases involved in the phosphorylation of ribosomal protein S6. J Biol Chem. 1991 Apr 5;266(10):6007–6010. [PubMed] [Google Scholar]
  23. Flotow H., Thomas G. Substrate recognition determinants of the mitogen-activated 70K S6 kinase from rat liver. J Biol Chem. 1992 Feb 15;267(5):3074–3078. [PubMed] [Google Scholar]
  24. Gale N. W., Kaplan S., Lowenstein E. J., Schlessinger J., Bar-Sagi D. Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras. Nature. 1993 May 6;363(6424):88–92. doi: 10.1038/363088a0. [DOI] [PubMed] [Google Scholar]
  25. Gotoh Y., Nishida E., Matsuda S., Shiina N., Kosako H., Shiokawa K., Akiyama T., Ohta K., Sakai H. In vitro effects on microtubule dynamics of purified Xenopus M phase-activated MAP kinase. Nature. 1991 Jan 17;349(6306):251–254. doi: 10.1038/349251a0. [DOI] [PubMed] [Google Scholar]
  26. Gout I., Dhand R., Hiles I. D., Fry M. J., Panayotou G., Das P., Truong O., Totty N. F., Hsuan J., Booker G. W. The GTPase dynamin binds to and is activated by a subset of SH3 domains. Cell. 1993 Oct 8;75(1):25–36. [PubMed] [Google Scholar]
  27. Hara K., Yonezawa K., Sakaue H., Ando A., Kotani K., Kitamura T., Kitamura Y., Ueda H., Stephens L., Jackson T. R. 1-Phosphatidylinositol 3-kinase activity is required for insulin-stimulated glucose transport but not for RAS activation in CHO cells. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7415–7419. doi: 10.1073/pnas.91.16.7415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Howe L. R., Leevers S. J., Gómez N., Nakielny S., Cohen P., Marshall C. J. Activation of the MAP kinase pathway by the protein kinase raf. Cell. 1992 Oct 16;71(2):335–342. doi: 10.1016/0092-8674(92)90361-f. [DOI] [PubMed] [Google Scholar]
  29. Kasuga M., Fujita-Yamaguchi Y., Blithe D. L., Kahn C. R. Tyrosine-specific protein kinase activity is associated with the purified insulin receptor. Proc Natl Acad Sci U S A. 1983 Apr;80(8):2137–2141. doi: 10.1073/pnas.80.8.2137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Koch C. A., Anderson D., Moran M. F., Ellis C., Pawson T. SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. Science. 1991 May 3;252(5006):668–674. doi: 10.1126/science.1708916. [DOI] [PubMed] [Google Scholar]
  31. Kotani K., Yonezawa K., Hara K., Ueda H., Kitamura Y., Sakaue H., Ando A., Chavanieu A., Calas B., Grigorescu F. Involvement of phosphoinositide 3-kinase in insulin- or IGF-1-induced membrane ruffling. EMBO J. 1994 May 15;13(10):2313–2321. doi: 10.1002/j.1460-2075.1994.tb06515.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Kozma S. C., Ferrari S., Bassand P., Siegmann M., Totty N., Thomas G. Cloning of the mitogen-activated S6 kinase from rat liver reveals an enzyme of the second messenger subfamily. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7365–7369. doi: 10.1073/pnas.87.19.7365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Kuhné M. R., Pawson T., Lienhard G. E., Feng G. S. The insulin receptor substrate 1 associates with the SH2-containing phosphotyrosine phosphatase Syp. J Biol Chem. 1993 Jun 5;268(16):11479–11481. [PubMed] [Google Scholar]
  34. Lane H. A., Fernandez A., Lamb N. J., Thomas G. p70s6k function is essential for G1 progression. Nature. 1993 May 13;363(6425):170–172. doi: 10.1038/363170a0. [DOI] [PubMed] [Google Scholar]
  35. Lavan B. E., Kuhné M. R., Garner C. W., Anderson D., Reedijk M., Pawson T., Lienhard G. E. The association of insulin-elicited phosphotyrosine proteins with src homology 2 domains. J Biol Chem. 1992 Jun 5;267(16):11631–11636. [PubMed] [Google Scholar]
  36. Lee C. H., Li W., Nishimura R., Zhou M., Batzer A. G., Myers M. G., Jr, White M. F., Schlessinger J., Skolnik E. Y. Nck associates with the SH2 domain-docking protein IRS-1 in insulin-stimulated cells. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11713–11717. doi: 10.1073/pnas.90.24.11713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Li N., Batzer A., Daly R., Yajnik V., Skolnik E., Chardin P., Bar-Sagi D., Margolis B., Schlessinger J. Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature. 1993 May 6;363(6424):85–88. doi: 10.1038/363085a0. [DOI] [PubMed] [Google Scholar]
  38. Lowenstein E. J., Daly R. J., Batzer A. G., Li W., Margolis B., Lammers R., Ullrich A., Skolnik E. Y., Bar-Sagi D., Schlessinger J. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell. 1992 Aug 7;70(3):431–442. doi: 10.1016/0092-8674(92)90167-b. [DOI] [PubMed] [Google Scholar]
  39. Matuoka K., Shibata M., Yamakawa A., Takenawa T. Cloning of ASH, a ubiquitous protein composed of one Src homology region (SH) 2 and two SH3 domains, from human and rat cDNA libraries. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9015–9019. doi: 10.1073/pnas.89.19.9015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Miki H., Miura K., Matuoka K., Nakata T., Hirokawa N., Orita S., Kaibuchi K., Takai Y., Takenawa T. Association of Ash/Grb-2 with dynamin through the Src homology 3 domain. J Biol Chem. 1994 Feb 25;269(8):5489–5492. [PubMed] [Google Scholar]
  41. Ming X. F., Burgering B. M., Wennström S., Claesson-Welsh L., Heldin C. H., Bos J. L., Kozma S. C., Thomas G. Activation of p70/p85 S6 kinase by a pathway independent of p21ras. Nature. 1994 Sep 29;371(6496):426–429. doi: 10.1038/371426a0. [DOI] [PubMed] [Google Scholar]
  42. Myers M. G., Jr, Wang L. M., Sun X. J., Zhang Y., Yenush L., Schlessinger J., Pierce J. H., White M. F. Role of IRS-1-GRB-2 complexes in insulin signaling. Mol Cell Biol. 1994 Jun;14(6):3577–3587. doi: 10.1128/mcb.14.6.3577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Nakafuku M., Satoh T., Kaziro Y. Differentiation factors, including nerve growth factor, fibroblast growth factor, and interleukin-6, induce an accumulation of an active Ras.GTP complex in rat pheochromocytoma PC12 cells. J Biol Chem. 1992 Sep 25;267(27):19448–19454. [PubMed] [Google Scholar]
  44. Noguchi T., Matozaki T., Horita K., Fujioka Y., Kasuga M. Role of SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in insulin-stimulated Ras activation. Mol Cell Biol. 1994 Oct;14(10):6674–6682. doi: 10.1128/mcb.14.10.6674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Posada J., Cooper J. A. Requirements for phosphorylation of MAP kinase during meiosis in Xenopus oocytes. Science. 1992 Jan 10;255(5041):212–215. doi: 10.1126/science.1313186. [DOI] [PubMed] [Google Scholar]
  46. Price D. J., Grove J. R., Calvo V., Avruch J., Bierer B. E. Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science. 1992 Aug 14;257(5072):973–977. doi: 10.1126/science.1380182. [DOI] [PubMed] [Google Scholar]
  47. Price D. J., Gunsalus J. R., Avruch J. Insulin activates a 70-kDa S6 kinase through serine/threonine-specific phosphorylation of the enzyme polypeptide. Proc Natl Acad Sci U S A. 1990 Oct;87(20):7944–7948. doi: 10.1073/pnas.87.20.7944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Pronk G. J., McGlade J., Pelicci G., Pawson T., Bos J. L. Insulin-induced phosphorylation of the 46- and 52-kDa Shc proteins. J Biol Chem. 1993 Mar 15;268(8):5748–5753. [PubMed] [Google Scholar]
  49. Pronk G. J., de Vries-Smits A. M., Buday L., Downward J., Maassen J. A., Medema R. H., Bos J. L. Involvement of Shc in insulin- and epidermal growth factor-induced activation of p21ras. Mol Cell Biol. 1994 Mar;14(3):1575–1581. doi: 10.1128/mcb.14.3.1575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Robinson L. J., Razzack Z. F., Lawrence J. C., Jr, James D. E. Mitogen-activated protein kinase activation is not sufficient for stimulation of glucose transport or glycogen synthase in 3T3-L1 adipocytes. J Biol Chem. 1993 Dec 15;268(35):26422–26427. [PubMed] [Google Scholar]
  51. Roth R. A., Cassell D. J. Insulin receptor: evidence that it is a protein kinase. Science. 1983 Jan 21;219(4582):299–301. doi: 10.1126/science.6849137. [DOI] [PubMed] [Google Scholar]
  52. 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 May 6;363(6424):83–85. doi: 10.1038/363083a0. [DOI] [PubMed] [Google Scholar]
  53. Rozakis-Adcock M., McGlade J., Mbamalu G., Pelicci G., Daly R., Li W., Batzer A., Thomas S., Brugge J., Pelicci P. G. Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases. Nature. 1992 Dec 17;360(6405):689–692. doi: 10.1038/360689a0. [DOI] [PubMed] [Google Scholar]
  54. Sasaoka T., Draznin B., Leitner J. W., Langlois W. J., Olefsky J. M. Shc is the predominant signaling molecule coupling insulin receptors to activation of guanine nucleotide releasing factor and p21ras-GTP formation. J Biol Chem. 1994 Apr 8;269(14):10734–10738. [PubMed] [Google Scholar]
  55. Sell C., Dumenil G., Deveaud C., Miura M., Coppola D., DeAngelis T., Rubin R., Efstratiadis A., Baserga R. Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts. Mol Cell Biol. 1994 Jun;14(6):3604–3612. doi: 10.1128/mcb.14.6.3604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Skolnik E. Y., Batzer A., Li N., Lee C. H., Lowenstein E., Mohammadi M., Margolis B., Schlessinger J. The function of GRB2 in linking the insulin receptor to Ras signaling pathways. Science. 1993 Jun 25;260(5116):1953–1955. doi: 10.1126/science.8316835. [DOI] [PubMed] [Google Scholar]
  57. Skolnik E. Y., Lee C. H., Batzer A., Vicentini L. M., Zhou M., Daly R., Myers M. J., Jr, Backer J. M., Ullrich A., White M. F. The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling. EMBO J. 1993 May;12(5):1929–1936. doi: 10.1002/j.1460-2075.1993.tb05842.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Sturgill T. W., Ray L. B., Erikson E., Maller J. L. Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II. Nature. 1988 Aug 25;334(6184):715–718. doi: 10.1038/334715a0. [DOI] [PubMed] [Google Scholar]
  59. Sun X. J., Rothenberg P., Kahn C. R., Backer J. M., Araki E., Wilden P. A., Cahill D. A., Goldstein B. J., White M. F. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature. 1991 Jul 4;352(6330):73–77. doi: 10.1038/352073a0. [DOI] [PubMed] [Google Scholar]
  60. Sutherland C., Campbell D. G., Cohen P. Identification of insulin-stimulated protein kinase-1 as the rabbit equivalent of rskmo-2. Identification of two threonines phosphorylated during activation by mitogen-activated protein kinase. Eur J Biochem. 1993 Mar 1;212(2):581–588. doi: 10.1111/j.1432-1033.1993.tb17696.x. [DOI] [PubMed] [Google Scholar]
  61. Sutherland C., Leighton I. A., Cohen P. Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem J. 1993 Nov 15;296(Pt 1):15–19. doi: 10.1042/bj2960015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Thomas J. A., Schlender K. K., Larner J. A rapid filter paper assay for UDPglucose-glycogen glucosyltransferase, including an improved biosynthesis of UDP-14C-glucose. Anal Biochem. 1968 Oct 24;25(1):486–499. doi: 10.1016/0003-2697(68)90127-9. [DOI] [PubMed] [Google Scholar]
  63. Uchida T., Matozaki T., Noguchi T., Yamao T., Horita K., Suzuki T., Fujioka Y., Sakamoto C., Kasuga M. Insulin stimulates the phosphorylation of Tyr538 and the catalytic activity of PTP1C, a protein tyrosine phosphatase with Src homology-2 domains. J Biol Chem. 1994 Apr 22;269(16):12220–12228. [PubMed] [Google Scholar]
  64. Yokota T., Coffman R. L., Hagiwara H., Rennick D. M., Takebe Y., Yokota K., Gemmell L., Shrader B., Yang G., Meyerson P. Isolation and characterization of lymphokine cDNA clones encoding mouse and human IgA-enhancing factor and eosinophil colony-stimulating factor activities: relationship to interleukin 5. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7388–7392. doi: 10.1073/pnas.84.21.7388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Yonezawa K., Ando A., Kaburagi Y., Yamamoto-Honda R., Kitamura T., Hara K., Nakafuku M., Okabayashi Y., Kadowaki T., Kaziro Y. Signal transduction pathways from insulin receptors to Ras. Analysis by mutant insulin receptors. J Biol Chem. 1994 Feb 11;269(6):4634–4640. [PubMed] [Google Scholar]
  66. Yonezawa K., Ueda H., Hara K., Nishida K., Ando A., Chavanieu A., Matsuba H., Shii K., Yokono K., Fukui Y. Insulin-dependent formation of a complex containing an 85-kDa subunit of phosphatidylinositol 3-kinase and tyrosine-phosphorylated insulin receptor substrate 1. J Biol Chem. 1992 Dec 25;267(36):25958–25965. [PubMed] [Google Scholar]
  67. de Vries-Smits A. M., Burgering B. M., Leevers S. J., Marshall C. J., Bos J. L. Involvement of p21ras in activation of extracellular signal-regulated kinase 2. Nature. 1992 Jun 18;357(6379):602–604. doi: 10.1038/357602a0. [DOI] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES