Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1998 May 1;17(9):2554–2565. doi: 10.1093/emboj/17.9.2554

Insulin regulates the dynamic balance between Ras and Rap1 signaling by coordinating the assembly states of the Grb2-SOS and CrkII-C3G complexes.

S Okada 1, M Matsuda 1, M Anafi 1, T Pawson 1, J E Pessin 1
PMCID: PMC1170597  PMID: 9564038

Abstract

Insulin stimulation of Chinese hamster ovary cells expressing the human insulin receptor resulted in a time-dependent decrease in the amount of GTP bound to Rap1. The inactivation of Rap1 was associated with an insulin-stimulated decrease in the amount of Rap1 that was bound to Raf1. In parallel with the dissociation of Raf1 from Rap1, there was an increased association of Raf1 with Ras. Concomitant with the inactivation of Rap1 and decrease in Rap1-Raf1 binding, we observed a rapid insulin-stimulated dissociation of the CrkII-C3G complex which occurred in a Ras-independent manner. The dissociation of the CrkII-C3G was recapitulated in vitro using a GST-C3G fusion protein to precipitate CrkII from whole cell detergent extracts. The association of GST-C3G with CrkII was also dose dependent and demonstrated that insulin reduced the affinity of CrkII for C3G without any effect on CrkII protein levels. Furthermore, the reduction in CrkII binding affinity was reversible by tyrosine dephosphorylation with PTP1B and by mutation of Tyr221 to phenylalanine. Together, these data demonstrate that insulin treatment results in the de-repression of Rap1 inhibitory function on the Raf1 kinase concomitant with Ras activation and stimulation of the downstream Raf1/MEK/ERK cascade.

Full Text

The Full Text of this article is available as a PDF (414.5 KB).

Selected References

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

  1. Altschuler D. L., Peterson S. N., Ostrowski M. C., Lapetina E. G. Cyclic AMP-dependent activation of Rap1b. J Biol Chem. 1995 May 5;270(18):10373–10376. doi: 10.1074/jbc.270.18.10373. [DOI] [PubMed] [Google Scholar]
  2. Anafi M., Rosen M. K., Gish G. D., Kay L. E., Pawson T. A potential SH3 domain-binding site in the Crk SH2 domain. J Biol Chem. 1996 Aug 30;271(35):21365–21374. doi: 10.1074/jbc.271.35.21365. [DOI] [PubMed] [Google Scholar]
  3. Avruch J., Zhang X. F., Kyriakis J. M. Raf meets Ras: completing the framework of a signal transduction pathway. Trends Biochem Sci. 1994 Jul;19(7):279–283. doi: 10.1016/0968-0004(94)90005-1. [DOI] [PubMed] [Google Scholar]
  4. Barnier J. V., Papin C., Eychène A., Lecoq O., Calothy G. The mouse B-raf gene encodes multiple protein isoforms with tissue-specific expression. J Biol Chem. 1995 Oct 6;270(40):23381–23389. doi: 10.1074/jbc.270.40.23381. [DOI] [PubMed] [Google Scholar]
  5. Beitner-Johnson D., Blakesley V. A., Shen-Orr Z., Jimenez M., Stannard B., Wang L. M., Pierce J., LeRoith D. The proto-oncogene product c-Crk associates with insulin receptor substrate-1 and 4PS. Modulation by insulin growth factor-I (IGF) and enhanced IGF-I signaling. J Biol Chem. 1996 Apr 19;271(16):9287–9290. doi: 10.1074/jbc.271.16.9287. [DOI] [PubMed] [Google Scholar]
  6. Beitner-Johnson D., LeRoith D. Insulin-like growth factor-I stimulates tyrosine phosphorylation of endogenous c-Crk. J Biol Chem. 1995 Mar 10;270(10):5187–5190. doi: 10.1074/jbc.270.10.5187. [DOI] [PubMed] [Google Scholar]
  7. Birge R. B., Fajardo J. E., Mayer B. J., Hanafusa H. Tyrosine-phosphorylated epidermal growth factor receptor and cellular p130 provide high affinity binding substrates to analyze Crk-phosphotyrosine-dependent interactions in vitro. J Biol Chem. 1992 May 25;267(15):10588–10595. [PubMed] [Google Scholar]
  8. Birge R. B., Fajardo J. E., Reichman C., Shoelson S. E., Songyang Z., Cantley L. C., Hanafusa H. Identification and characterization of a high-affinity interaction between v-Crk and tyrosine-phosphorylated paxillin in CT10-transformed fibroblasts. Mol Cell Biol. 1993 Aug;13(8):4648–4656. doi: 10.1128/mcb.13.8.4648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Blenis J. Signal transduction via the MAP kinases: proceed at your own RSK. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5889–5892. doi: 10.1073/pnas.90.13.5889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Blumer K. J., Johnson G. L. Diversity in function and regulation of MAP kinase pathways. Trends Biochem Sci. 1994 Jun;19(6):236–240. doi: 10.1016/0968-0004(94)90147-3. [DOI] [PubMed] [Google Scholar]
  11. Bokoch G. M. Biology of the Rap proteins, members of the ras superfamily of GTP-binding proteins. Biochem J. 1993 Jan 1;289(Pt 1):17–24. doi: 10.1042/bj2890017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Burgering B. M., Bos J. L. Regulation of Ras-mediated signalling: more than one way to skin a cat. Trends Biochem Sci. 1995 Jan;20(1):18–22. doi: 10.1016/s0968-0004(00)88944-6. [DOI] [PubMed] [Google Scholar]
  13. Chardin P., Cussac D., Maignan S., Ducruix A. The Grb2 adaptor. FEBS Lett. 1995 Aug 1;369(1):47–51. doi: 10.1016/0014-5793(95)00578-w. [DOI] [PubMed] [Google Scholar]
  14. Chen D., Elmendorf J. S., Olson A. L., Li X., Earp H. S., Pessin J. E. Osmotic shock stimulates GLUT4 translocation in 3T3L1 adipocytes by a novel tyrosine kinase pathway. J Biol Chem. 1997 Oct 24;272(43):27401–27410. doi: 10.1074/jbc.272.43.27401. [DOI] [PubMed] [Google Scholar]
  15. Cherniack A. D., Klarlund J. K., Conway B. R., Czech M. P. Disassembly of Son-of-sevenless proteins from Grb2 during p21ras desensitization by insulin. J Biol Chem. 1995 Jan 27;270(4):1485–1488. [PubMed] [Google Scholar]
  16. Cook S. J., Rubinfeld B., Albert I., McCormick F. RapV12 antagonizes Ras-dependent activation of ERK1 and ERK2 by LPA and EGF in Rat-1 fibroblasts. EMBO J. 1993 Sep;12(9):3475–3485. doi: 10.1002/j.1460-2075.1993.tb06022.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Davis R. J. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem. 1993 Jul 15;268(20):14553–14556. [PubMed] [Google Scholar]
  18. Dent P., Jelinek T., Morrison D. K., Weber M. J., Sturgill T. W. Reversal of Raf-1 activation by purified and membrane-associated protein phosphatases. Science. 1995 Jun 30;268(5219):1902–1906. doi: 10.1126/science.7604263. [DOI] [PubMed] [Google Scholar]
  19. Diaz B., Barnard D., Filson A., MacDonald S., King A., Marshall M. Phosphorylation of Raf-1 serine 338-serine 339 is an essential regulatory event for Ras-dependent activation and biological signaling. Mol Cell Biol. 1997 Aug;17(8):4509–4516. doi: 10.1128/mcb.17.8.4509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Downward J. Control of ras activation. Cancer Surv. 1996;27:87–100. [PubMed] [Google Scholar]
  21. Downward J. The GRB2/Sem-5 adaptor protein. FEBS Lett. 1994 Jan 31;338(2):113–117. doi: 10.1016/0014-5793(94)80346-3. [DOI] [PubMed] [Google Scholar]
  22. Fabian J. R., Daar I. O., Morrison D. K. Critical tyrosine residues regulate the enzymatic and biological activity of Raf-1 kinase. Mol Cell Biol. 1993 Nov;13(11):7170–7179. doi: 10.1128/mcb.13.11.7170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Feller S. M., Knudsen B., Hanafusa H. Cellular proteins binding to the first Src homology 3 (SH3) domain of the proto-oncogene product c-Crk indicate Crk-specific signaling pathways. Oncogene. 1995 Apr 20;10(8):1465–1473. [PubMed] [Google Scholar]
  24. Feller S. M., Knudsen B., Hanafusa H. c-Abl kinase regulates the protein binding activity of c-Crk. EMBO J. 1994 May 15;13(10):2341–2351. doi: 10.1002/j.1460-2075.1994.tb06518.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Franke B., Akkerman J. W., Bos J. L. Rapid Ca2+-mediated activation of Rap1 in human platelets. EMBO J. 1997 Jan 15;16(2):252–259. doi: 10.1093/emboj/16.2.252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Frattali A. L., Treadway J. L., Pessin J. E. Evidence supporting a passive role for the insulin receptor transmembrane domain in insulin-dependent signal transduction. J Biol Chem. 1991 May 25;266(15):9829–9834. [PubMed] [Google Scholar]
  27. Frech M., John J., Pizon V., Chardin P., Tavitian A., Clark R., McCormick F., Wittinghofer A. Inhibition of GTPase activating protein stimulation of Ras-p21 GTPase by the Krev-1 gene product. Science. 1990 Jul 13;249(4965):169–171. doi: 10.1126/science.2164710. [DOI] [PubMed] [Google Scholar]
  28. Gotoh T., Hattori S., Nakamura S., Kitayama H., Noda M., Takai Y., Kaibuchi K., Matsui H., Hatase O., Takahashi H. Identification of Rap1 as a target for the Crk SH3 domain-binding guanine nucleotide-releasing factor C3G. Mol Cell Biol. 1995 Dec;15(12):6746–6753. doi: 10.1128/mcb.15.12.6746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Hasegawa H., Kiyokawa E., Tanaka S., Nagashima K., Gotoh N., Shibuya M., Kurata T., Matsuda M. DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane. Mol Cell Biol. 1996 Apr;16(4):1770–1776. doi: 10.1128/mcb.16.4.1770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Hata Y., Kikuchi A., Sasaki T., Schaber M. D., Gibbs J. B., Takai Y. Inhibition of the ras p21 GTPase-activating protein-stimulated GTPase activity of c-Ha-ras p21 by smg p21 having the same putative effector domain as ras p21s. J Biol Chem. 1990 May 5;265(13):7104–7107. [PubMed] [Google Scholar]
  31. Hempstead B. L., Birge R. B., Fajardo J. E., Glassman R., Mahadeo D., Kraemer R., Hanafusa H. Expression of the v-crk oncogene product in PC12 cells results in rapid differentiation by both nerve growth factor- and epidermal growth factor-dependent pathways. Mol Cell Biol. 1994 Mar;14(3):1964–1971. doi: 10.1128/mcb.14.3.1964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Herrmann C., Horn G., Spaargaren M., Wittinghofer A. Differential interaction of the ras family GTP-binding proteins H-Ras, Rap1A, and R-Ras with the putative effector molecules Raf kinase and Ral-guanine nucleotide exchange factor. J Biol Chem. 1996 Mar 22;271(12):6794–6800. doi: 10.1074/jbc.271.12.6794. [DOI] [PubMed] [Google Scholar]
  33. Hill C. S., Treisman R. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell. 1995 Jan 27;80(2):199–211. doi: 10.1016/0092-8674(95)90403-4. [DOI] [PubMed] [Google Scholar]
  34. Holt K. H., Kasson B. G., Pessin J. E. Insulin stimulation of a MEK-dependent but ERK-independent SOS protein kinase. Mol Cell Biol. 1996 Feb;16(2):577–583. doi: 10.1128/mcb.16.2.577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Holt K. H., Waters S. B., Okada S., Yamauchi K., Decker S. J., Saltiel A. R., Motto D. G., Koretzky G. A., Pessin J. E. Epidermal growth factor receptor targeting prevents uncoupling of the Grb2-SOS complex. J Biol Chem. 1996 Apr 5;271(14):8300–8306. doi: 10.1074/jbc.271.14.8300. [DOI] [PubMed] [Google Scholar]
  36. Hu C. D., Kariya K. i., Kotani G., Shirouzu M., Yokoyama S., Kataoka T. Coassociation of Rap1A and Ha-Ras with Raf-1 N-terminal region interferes with ras-dependent activation of Raf-1. J Biol Chem. 1997 May 2;272(18):11702–11705. doi: 10.1074/jbc.272.18.11702. [DOI] [PubMed] [Google Scholar]
  37. Ichiba T., Kuraishi Y., Sakai O., Nagata S., Groffen J., Kurata T., Hattori S., Matsuda M. Enhancement of guanine-nucleotide exchange activity of C3G for Rap1 by the expression of Crk, CrkL, and Grb2. J Biol Chem. 1997 Aug 29;272(35):22215–22220. doi: 10.1074/jbc.272.35.22215. [DOI] [PubMed] [Google Scholar]
  38. Ingham R. J., Krebs D. L., Barbazuk S. M., Turck C. W., Hirai H., Matsuda M., Gold M. R. B cell antigen receptor signaling induces the formation of complexes containing the Crk adapter proteins. J Biol Chem. 1996 Dec 13;271(50):32306–32314. doi: 10.1074/jbc.271.50.32306. [DOI] [PubMed] [Google Scholar]
  39. Ishiki M., Sasaoka T., Ishihara H., Imamura T., Usui I., Takata Y., Kobayashi M. Evidence for functional roles of Crk-II in insulin and epidermal growth factor signaling in Rat-1 fibroblasts overexpressing insulin receptors. Endocrinology. 1997 Nov;138(11):4950–4958. doi: 10.1210/endo.138.11.5510. [DOI] [PubMed] [Google Scholar]
  40. Jelinek M. A., Hassell J. A. Reversion of middle T antigen-transformed Rat-2 cells by Krev-1: implications for the role of p21c-ras in polyomavirus-mediated transformation. Oncogene. 1992 Sep;7(9):1687–1698. [PubMed] [Google Scholar]
  41. Jelinek T., Dent P., Sturgill T. W., Weber M. J. Ras-induced activation of Raf-1 is dependent on tyrosine phosphorylation. Mol Cell Biol. 1996 Mar;16(3):1027–1034. doi: 10.1128/mcb.16.3.1027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Kahn C. R. Banting Lecture. Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes. 1994 Aug;43(8):1066–1084. doi: 10.2337/diab.43.8.1066. [DOI] [PubMed] [Google Scholar]
  43. Kao A. W., Waters S. B., Okada S., Pessin J. E. Insulin stimulates the phosphorylation of the 66- and 52-kilodalton Shc isoforms by distinct pathways. Endocrinology. 1997 Jun;138(6):2474–2480. doi: 10.1210/endo.138.6.5203. [DOI] [PubMed] [Google Scholar]
  44. Kitayama H., Sugimoto Y., Matsuzaki T., Ikawa Y., Noda M. A ras-related gene with transformation suppressor activity. Cell. 1989 Jan 13;56(1):77–84. doi: 10.1016/0092-8674(89)90985-9. [DOI] [PubMed] [Google Scholar]
  45. Knudsen B. S., Feller S. M., Hanafusa H. Four proline-rich sequences of the guanine-nucleotide exchange factor C3G bind with unique specificity to the first Src homology 3 domain of Crk. J Biol Chem. 1994 Dec 30;269(52):32781–32787. [PubMed] [Google Scholar]
  46. Langlois W. J., Sasaoka T., Saltiel A. R., Olefsky J. M. Negative feedback regulation and desensitization of insulin- and epidermal growth factor-stimulated p21ras activation. J Biol Chem. 1995 Oct 27;270(43):25320–25323. doi: 10.1074/jbc.270.43.25320. [DOI] [PubMed] [Google Scholar]
  47. 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]
  48. Maassen J. A., Burgering B. M., Medema R. H., Osterop A. P., van der Zon G. C., Möller W., Bos J. L. The role of ras proteins in insulin signal transduction. Horm Metab Res. 1992 May;24(5):214–218. doi: 10.1055/s-2007-1003296. [DOI] [PubMed] [Google Scholar]
  49. Marshall C. J. MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. Curr Opin Genet Dev. 1994 Feb;4(1):82–89. doi: 10.1016/0959-437x(94)90095-7. [DOI] [PubMed] [Google Scholar]
  50. Matsuda M., Hashimoto Y., Muroya K., Hasegawa H., Kurata T., Tanaka S., Nakamura S., Hattori S. CRK protein binds to two guanine nucleotide-releasing proteins for the Ras family and modulates nerve growth factor-induced activation of Ras in PC12 cells. Mol Cell Biol. 1994 Aug;14(8):5495–5500. doi: 10.1128/mcb.14.8.5495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Matsuda M., Mayer B. J., Fukui Y., Hanafusa H. Binding of transforming protein, P47gag-crk, to a broad range of phosphotyrosine-containing proteins. Science. 1990 Jun 22;248(4962):1537–1539. doi: 10.1126/science.1694307. [DOI] [PubMed] [Google Scholar]
  52. Matsuda M., Tanaka S., Nagata S., Kojima A., Kurata T., Shibuya M. Two species of human CRK cDNA encode proteins with distinct biological activities. Mol Cell Biol. 1992 Aug;12(8):3482–3489. doi: 10.1128/mcb.12.8.3482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Mayer B. J., Hamaguchi M., Hanafusa H. A novel viral oncogene with structural similarity to phospholipase C. Nature. 1988 Mar 17;332(6161):272–275. doi: 10.1038/332272a0. [DOI] [PubMed] [Google Scholar]
  54. Medema R. H., Bos J. L. The role of p21ras in receptor tyrosine kinase signaling. Crit Rev Oncog. 1993;4(6):615–661. [PubMed] [Google Scholar]
  55. Moarefi I., LaFevre-Bernt M., Sicheri F., Huse M., Lee C. H., Kuriyan J., Miller W. T. Activation of the Src-family tyrosine kinase Hck by SH3 domain displacement. Nature. 1997 Feb 13;385(6617):650–653. doi: 10.1038/385650a0. [DOI] [PubMed] [Google Scholar]
  56. Moodie S. A., Willumsen B. M., Weber M. J., Wolfman A. Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase. Science. 1993 Jun 11;260(5114):1658–1661. doi: 10.1126/science.8503013. [DOI] [PubMed] [Google Scholar]
  57. Nassar N., Horn G., Herrmann C., Scherer A., McCormick F., Wittinghofer A. The 2.2 A crystal structure of the Ras-binding domain of the serine/threonine kinase c-Raf1 in complex with Rap1A and a GTP analogue. Nature. 1995 Jun 15;375(6532):554–560. doi: 10.1038/375554a0. [DOI] [PubMed] [Google Scholar]
  58. Okada S., Pessin J. E. Interactions between Src homology (SH) 2/SH3 adapter proteins and the guanylnucleotide exchange factor SOS are differentially regulated by insulin and epidermal growth factor. J Biol Chem. 1996 Oct 11;271(41):25533–25538. doi: 10.1074/jbc.271.41.25533. [DOI] [PubMed] [Google Scholar]
  59. Perrimon N. Signalling pathways initiated by receptor protein tyrosine kinases in Drosophila. Curr Opin Cell Biol. 1994 Apr;6(2):260–266. doi: 10.1016/0955-0674(94)90145-7. [DOI] [PubMed] [Google Scholar]
  60. Pizon V., Chardin P., Lerosey I., Olofsson B., Tavitian A. Human cDNAs rap1 and rap2 homologous to the Drosophila gene Dras3 encode proteins closely related to ras in the 'effector' region. Oncogene. 1988 Aug;3(2):201–204. [PubMed] [Google Scholar]
  61. Polte T. R., Hanks S. K. Interaction between focal adhesion kinase and Crk-associated tyrosine kinase substrate p130Cas. Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10678–10682. doi: 10.1073/pnas.92.23.10678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Reichman C. T., Mayer B. J., Keshav S., Hanafusa H. The product of the cellular crk gene consists primarily of SH2 and SH3 regions. Cell Growth Differ. 1992 Jul;3(7):451–460. [PubMed] [Google Scholar]
  63. Ribon V., Hubbell S., Herrera R., Saltiel A. R. The product of the cbl oncogene forms stable complexes in vivo with endogenous Crk in a tyrosine phosphorylation-dependent manner. Mol Cell Biol. 1996 Jan;16(1):45–52. doi: 10.1128/mcb.16.1.45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Ribon V., Saltiel A. R. Nerve growth factor stimulates the tyrosine phosphorylation of endogenous Crk-II and augments its association with p130Cas in PC-12 cells. J Biol Chem. 1996 Mar 29;271(13):7375–7380. doi: 10.1074/jbc.271.13.7375. [DOI] [PubMed] [Google Scholar]
  65. Rosen M. K., Yamazaki T., Gish G. D., Kay C. M., Pawson T., Kay L. E. Direct demonstration of an intramolecular SH2-phosphotyrosine interaction in the Crk protein. Nature. 1995 Mar 30;374(6521):477–479. doi: 10.1038/374477a0. [DOI] [PubMed] [Google Scholar]
  66. Roth R. A., Liu F., Chin J. E. Biochemical mechanisms of insulin resistance. Horm Res. 1994;41 (Suppl 2):51–55. doi: 10.1159/000183961. [DOI] [PubMed] [Google Scholar]
  67. 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]
  68. Ruggieri R., Macdonald S. G., Callow M., McCormick F. Raf-1 interferes with Ras and Rap1A effector functions in yeast. Mol Biol Cell. 1994 Feb;5(2):173–181. doi: 10.1091/mbc.5.2.173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Sakai R., Iwamatsu A., Hirano N., Ogawa S., Tanaka T., Mano H., Yazaki Y., Hirai H. A novel signaling molecule, p130, forms stable complexes in vivo with v-Crk and v-Src in a tyrosine phosphorylation-dependent manner. EMBO J. 1994 Aug 15;13(16):3748–3756. doi: 10.1002/j.1460-2075.1994.tb06684.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Sakoda T., Kaibuchi K., Kishi K., Kishida S., Doi K., Hoshino M., Hattori S., Takai Y. smg/rap1/Krev-1 p21s inhibit the signal pathway to the c-fos promoter/enhancer from c-Ki-ras p21 but not from c-raf-1 kinase in NIH3T3 cells. Oncogene. 1992 Sep;7(9):1705–1711. [PubMed] [Google Scholar]
  71. Schaller M. D., Otey C. A., Hildebrand J. D., Parsons J. T. Focal adhesion kinase and paxillin bind to peptides mimicking beta integrin cytoplasmic domains. J Cell Biol. 1995 Sep;130(5):1181–1187. doi: 10.1083/jcb.130.5.1181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Schaller M. D., Parsons J. T. pp125FAK-dependent tyrosine phosphorylation of paxillin creates a high-affinity binding site for Crk. Mol Cell Biol. 1995 May;15(5):2635–2645. doi: 10.1128/mcb.15.5.2635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Schieffer B., Paxton W. G., Chai Q., Marrero M. B., Bernstein K. E. Angiotensin II controls p21ras activity via pp60c-src. J Biol Chem. 1996 Apr 26;271(17):10329–10333. doi: 10.1074/jbc.271.17.10329. [DOI] [PubMed] [Google Scholar]
  74. Schumacher C., Knudsen B. S., Ohuchi T., Di Fiore P. P., Glassman R. H., Hanafusa H. The SH3 domain of Crk binds specifically to a conserved proline-rich motif in Eps15 and Eps15R. J Biol Chem. 1995 Jun 23;270(25):15341–15347. doi: 10.1074/jbc.270.25.15341. [DOI] [PubMed] [Google Scholar]
  75. Sicheri F., Moarefi I., Kuriyan J. Crystal structure of the Src family tyrosine kinase Hck. Nature. 1997 Feb 13;385(6617):602–609. doi: 10.1038/385602a0. [DOI] [PubMed] [Google Scholar]
  76. Spaargaren M., Bischoff J. R. Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12609–12613. doi: 10.1073/pnas.91.26.12609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Sprang S. R. How Ras works: structure of a Rap-Raf complex. Structure. 1995 Jul 15;3(7):641–643. doi: 10.1016/s0969-2126(01)00198-8. [DOI] [PubMed] [Google Scholar]
  78. Tanaka S., Morishita T., Hashimoto Y., Hattori S., Nakamura S., Shibuya M., Matuoka K., Takenawa T., Kurata T., Nagashima K. C3G, a guanine nucleotide-releasing protein expressed ubiquitously, binds to the Src homology 3 domains of CRK and GRB2/ASH proteins. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3443–3447. doi: 10.1073/pnas.91.8.3443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Teng K. K., Lander H., Fajardo J. E., Hanafusa H., Hempstead B. L., Birge R. B. v-Crk modulation of growth factor-induced PC12 cell differentiation involves the Src homology 2 domain of v-Crk and sustained activation of the Ras/mitogen-activated protein kinase pathway. J Biol Chem. 1995 Sep 1;270(35):20677–20685. doi: 10.1074/jbc.270.35.20677. [DOI] [PubMed] [Google Scholar]
  80. Treisman R. Ternary complex factors: growth factor regulated transcriptional activators. Curr Opin Genet Dev. 1994 Feb;4(1):96–101. doi: 10.1016/0959-437x(94)90097-3. [DOI] [PubMed] [Google Scholar]
  81. Van Aelst L., Barr M., Marcus S., Polverino A., Wigler M. Complex formation between RAS and RAF and other protein kinases. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6213–6217. doi: 10.1073/pnas.90.13.6213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Vojtek A. B., Hollenberg S. M., Cooper J. A. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell. 1993 Jul 16;74(1):205–214. doi: 10.1016/0092-8674(93)90307-c. [DOI] [PubMed] [Google Scholar]
  83. Vossler M. R., Yao H., York R. D., Pan M. G., Rim C. S., Stork P. J. cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway. Cell. 1997 Apr 4;89(1):73–82. doi: 10.1016/s0092-8674(00)80184-1. [DOI] [PubMed] [Google Scholar]
  84. Vuori K., Hirai H., Aizawa S., Ruoslahti E. Introduction of p130cas signaling complex formation upon integrin-mediated cell adhesion: a role for Src family kinases. Mol Cell Biol. 1996 Jun;16(6):2606–2613. doi: 10.1128/mcb.16.6.2606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Warne P. H., Viciana P. R., Downward J. Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature. 1993 Jul 22;364(6435):352–355. doi: 10.1038/364352a0. [DOI] [PubMed] [Google Scholar]
  86. Waters S. B., Holt K. H., Ross S. E., Syu L. J., Guan K. L., Saltiel A. R., Koretzky G. A., Pessin J. E. Desensitization of Ras activation by a feedback disassociation of the SOS-Grb2 complex. J Biol Chem. 1995 Sep 8;270(36):20883–20886. doi: 10.1074/jbc.270.36.20883. [DOI] [PubMed] [Google Scholar]
  87. Waters S. B., Yamauchi K., Pessin J. E. Insulin-stimulated disassociation of the SOS-Grb2 complex. Mol Cell Biol. 1995 May;15(5):2791–2799. doi: 10.1128/mcb.15.5.2791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Williams N. G., Roberts T. M., Li P. Both p21ras and pp60v-src are required, but neither alone is sufficient, to activate the Raf-1 kinase. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2922–2926. doi: 10.1073/pnas.89.7.2922. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Xu W., Harrison S. C., Eck M. J. Three-dimensional structure of the tyrosine kinase c-Src. Nature. 1997 Feb 13;385(6617):595–602. doi: 10.1038/385595a0. [DOI] [PubMed] [Google Scholar]
  90. Yamauchi K., Pessin J. E. Insulin receptor substrate-1 (IRS1) and Shc compete for a limited pool of Grb2 in mediating insulin downstream signaling. J Biol Chem. 1994 Dec 9;269(49):31107–31114. [PubMed] [Google Scholar]
  91. Yatani A., Quilliam L. A., Brown A. M., Bokoch G. M. Rap1A antagonizes the ability of Ras and Ras-Gap to inhibit muscarinic K+ channels. J Biol Chem. 1991 Nov 25;266(33):22222–22226. [PubMed] [Google Scholar]
  92. Yoshida Y., Kawata M., Miura Y., Musha T., Sasaki T., Kikuchi A., Takai Y. Microinjection of smg/rap1/Krev-1 p21 into Swiss 3T3 cells induces DNA synthesis and morphological changes. Mol Cell Biol. 1992 Aug;12(8):3407–3414. doi: 10.1128/mcb.12.8.3407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Zhang K., Noda M., Vass W. C., Papageorge A. G., Lowy D. R. Identification of small clusters of divergent amino acids that mediate the opposing effects of ras and Krev-1. Science. 1990 Jul 13;249(4965):162–165. doi: 10.1126/science.2115210. [DOI] [PubMed] [Google Scholar]
  94. Zhang X. F., Settleman J., Kyriakis J. M., Takeuchi-Suzuki E., Elledge S. J., Marshall M. S., Bruder J. T., Rapp U. R., Avruch J. Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature. 1993 Jul 22;364(6435):308–313. doi: 10.1038/364308a0. [DOI] [PubMed] [Google Scholar]
  95. ten Hoeve J., Kaartinen V., Fioretos T., Haataja L., Voncken J. W., Heisterkamp N., Groffen J. Cellular interactions of CRKL, and SH2-SH3 adaptor protein. Cancer Res. 1994 May 15;54(10):2563–2567. [PubMed] [Google Scholar]
  96. van der Geer P., Wiley S., Gish G. D., Pawson T. The Shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (Y239/240) that mediate protein-protein interactions. Curr Biol. 1996 Nov 1;6(11):1435–1444. doi: 10.1016/s0960-9822(96)00748-8. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES