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. 1995 Jun;15(6):3049–3057. doi: 10.1128/mcb.15.6.3049

Interleukin-2 triggers a novel phosphatidylinositol 3-kinase-dependent MEK activation pathway.

L M Karnitz 1, L A Burns 1, S L Sutor 1, J Blenis 1, R T Abraham 1
PMCID: PMC230536  PMID: 7760801

Abstract

Phosphatidylinositol 3-kinase (PI3-K) has been implicated as a signal-transducing component in interleukin-2 (IL-2)-induced mitogenesis. However, the function of this lipid kinase in regulating IL-2-triggered downstream events has remained obscure. Using the potent and specific PI3-K inhibitor, wortmannin, we assessed the role of PI3-K in IL-2-mediated signaling and proliferation in the murine T-cell line CTLL-2. Addition of the drug to exponentially growing cells resulted in an accumulation of cells in the G0/G1 phase of the cell cycle. Furthermore, wortmannin also partially suppressed IL-2-induced S-phase entry in G1-synchronized cells. Analysis of IL-2-triggered signaling pathways revealed that wortmannin pretreatment resulted in complete inhibition of IL-2-provoked p70 S6 kinase activation and also attenuated IL-2-induced MAP kinase activation at drug concentrations identical to those required for inhibition of PI3-K catalytic activity. Wortmannin also diminished the IL-2-triggered activation of the MAP kinase activator, MEK, but did not inhibit activation of Raf, the canonical upstream activator of MEK. These results suggest that a novel wortmannin-sensitive activation pathway regulates MEK and MAP kinase in IL-2-stimulated T lymphocytes.

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Selected References

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  1. Abraham R. T., Karnitz L. M., Burns L. A., Brunn G. J. Proximal signals and the control of S-phase entry in interleukin-2-stimulated T lymphocytes. Adv Exp Med Biol. 1994;365:197–210. doi: 10.1007/978-1-4899-0987-9_20. [DOI] [PubMed] [Google Scholar]
  2. Anderson N. G., Kilgour E., Sturgill T. W. Activation of mitogen-activated protein kinase in BC3H1 myocytes by fluoroaluminate. J Biol Chem. 1991 Jun 5;266(16):10131–10135. [PubMed] [Google Scholar]
  3. Augustine J. A., Sutor S. L., Abraham R. T. Interleukin 2- and polyomavirus middle T antigen-induced modification of phosphatidylinositol 3-kinase activity in activated T lymphocytes. Mol Cell Biol. 1991 Sep;11(9):4431–4440. doi: 10.1128/mcb.11.9.4431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bierer B. E., Mattila P. S., Standaert R. F., Herzenberg L. A., Burakoff S. J., Crabtree G., Schreiber S. L. Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9231–9235. doi: 10.1073/pnas.87.23.9231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bonnema J. D., Karnitz L. M., Schoon R. A., Abraham R. T., Leibson P. J. Fc receptor stimulation of phosphatidylinositol 3-kinase in natural killer cells is associated with protein kinase C-independent granule release and cell-mediated cytotoxicity. J Exp Med. 1994 Oct 1;180(4):1427–1435. doi: 10.1084/jem.180.4.1427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. Burns L. A., Karnitz L. M., Sutor S. L., Abraham R. T. Interleukin-2-induced tyrosine phosphorylation of p52shc in T lymphocytes. J Biol Chem. 1993 Aug 25;268(24):17659–17661. [PubMed] [Google Scholar]
  8. Calvo V., Crews C. M., Vik T. A., Bierer B. E. Interleukin 2 stimulation of p70 S6 kinase activity is inhibited by the immunosuppressant rapamycin. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7571–7575. doi: 10.1073/pnas.89.16.7571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cantrell D. A., Smith K. A. The interleukin-2 T-cell system: a new cell growth model. Science. 1984 Jun 22;224(4655):1312–1316. doi: 10.1126/science.6427923. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. 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]
  13. Crews C. M., Alessandrini A., Erikson R. L. The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science. 1992 Oct 16;258(5081):478–480. doi: 10.1126/science.1411546. [DOI] [PubMed] [Google Scholar]
  14. Downes C. P., Carter A. N. Phosphoinositide 3-kinase: a new effector in signal transduction? Cell Signal. 1991;3(6):501–513. doi: 10.1016/0898-6568(91)90027-r. [DOI] [PubMed] [Google Scholar]
  15. Dumont F. J., Melino M. R., Staruch M. J., Koprak S. L., Fischer P. A., Sigal N. H. The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T cells. J Immunol. 1990 Feb 15;144(4):1418–1424. [PubMed] [Google Scholar]
  16. Duronio V., Welham M. J., Abraham S., Dryden P., Schrader J. W. p21ras activation via hemopoietin receptors and c-kit requires tyrosine kinase activity but not tyrosine phosphorylation of p21ras GTPase-activating protein. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1587–1591. doi: 10.1073/pnas.89.5.1587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. Furth M. E., Davis L. J., Fleurdelys B., Scolnick E. M. Monoclonal antibodies to the p21 products of the transforming gene of Harvey murine sarcoma virus and of the cellular ras gene family. J Virol. 1982 Jul;43(1):294–304. doi: 10.1128/jvi.43.1.294-304.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hatakeyama M., Kono T., Kobayashi N., Kawahara A., Levin S. D., Perlmutter R. M., Taniguchi T. Interaction of the IL-2 receptor with the src-family kinase p56lck: identification of novel intermolecular association. Science. 1991 Jun 14;252(5012):1523–1528. doi: 10.1126/science.2047859. [DOI] [PubMed] [Google Scholar]
  20. Ho S. N., Abraham R. T., Gillis S., McKean D. J. Differential bioassay of interleukin 2 and interleukin 4. J Immunol Methods. 1987 Apr 2;98(1):99–104. doi: 10.1016/0022-1759(87)90441-8. [DOI] [PubMed] [Google Scholar]
  21. Horak I. D., Gress R. E., Lucas P. J., Horak E. M., Waldmann T. A., Bolen J. B. T-lymphocyte interleukin 2-dependent tyrosine protein kinase signal transduction involves the activation of p56lck. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1996–2000. doi: 10.1073/pnas.88.5.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Johnston J. A., Kawamura M., Kirken R. A., Chen Y. Q., Blake T. B., Shibuya K., Ortaldo J. R., McVicar D. W., O'Shea J. J. Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature. 1994 Jul 14;370(6485):151–153. doi: 10.1038/370151a0. [DOI] [PubMed] [Google Scholar]
  23. Joly M., Kazlauskas A., Fay F. S., Corvera S. Disruption of PDGF receptor trafficking by mutation of its PI-3 kinase binding sites. Science. 1994 Feb 4;263(5147):684–687. doi: 10.1126/science.8303278. [DOI] [PubMed] [Google Scholar]
  24. Karnitz L. M., Sutor S. L., Abraham R. T. The Src-family kinase, Fyn, regulates the activation of phosphatidylinositol 3-kinase in an interleukin 2-responsive T cell line. J Exp Med. 1994 Jun 1;179(6):1799–1808. doi: 10.1084/jem.179.6.1799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Karnitz L., Sutor S. L., Torigoe T., Reed J. C., Bell M. P., McKean D. J., Leibson P. J., Abraham R. T. Effects of p56lck deficiency on the growth and cytolytic effector function of an interleukin-2-dependent cytotoxic T-cell line. Mol Cell Biol. 1992 Oct;12(10):4521–4530. doi: 10.1128/mcb.12.10.4521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kobayashi N., Kono T., Hatakeyama M., Minami Y., Miyazaki T., Perlmutter R. M., Taniguchi T. Functional coupling of the src-family protein tyrosine kinases p59fyn and p53/56lyn with the interleukin 2 receptor: implications for redundancy and pleiotropism in cytokine signal transduction. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4201–4205. doi: 10.1073/pnas.90.9.4201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kuo C. J., Chung J., Fiorentino D. F., Flanagan W. M., Blenis J., Crabtree G. R. Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature. 1992 Jul 2;358(6381):70–73. doi: 10.1038/358070a0. [DOI] [PubMed] [Google Scholar]
  28. Lange-Carter C. A., Johnson G. L. Ras-dependent growth factor regulation of MEK kinase in PC12 cells. Science. 1994 Sep 2;265(5177):1458–1461. doi: 10.1126/science.8073291. [DOI] [PubMed] [Google Scholar]
  29. Lange-Carter C. A., Pleiman C. M., Gardner A. M., Blumer K. J., Johnson G. L. A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science. 1993 Apr 16;260(5106):315–319. doi: 10.1126/science.8385802. [DOI] [PubMed] [Google Scholar]
  30. Leevers S. J., Paterson H. F., Marshall C. J. Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature. 1994 Jun 2;369(6479):411–414. doi: 10.1038/369411a0. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Ling L. E., Druker B. J., Cantley L. C., Roberts T. M. Transformation-defective mutants of polyomavirus middle T antigen associate with phosphatidylinositol 3-kinase (PI 3-kinase) but are unable to maintain wild-type levels of PI 3-kinase products in intact cells. J Virol. 1992 Mar;66(3):1702–1708. doi: 10.1128/jvi.66.3.1702-1708.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Macdonald S. G., Crews C. M., Wu L., Driller J., Clark R., Erikson R. L., McCormick F. Reconstitution of the Raf-1-MEK-ERK signal transduction pathway in vitro. Mol Cell Biol. 1993 Nov;13(11):6615–6620. doi: 10.1128/mcb.13.11.6615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. 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]
  35. Merida I., Diez E., Gaulton G. N. IL-2 binding activates a tyrosine-phosphorylated phosphatidylinositol-3-kinase. J Immunol. 1991 Oct 1;147(7):2202–2207. [PubMed] [Google Scholar]
  36. Minami Y., Kono T., Yamada K., Kobayashi N., Kawahara A., Perlmutter R. M., Taniguchi T. Association of p56lck with IL-2 receptor beta chain is critical for the IL-2-induced activation of p56lck. EMBO J. 1993 Feb;12(2):759–768. doi: 10.1002/j.1460-2075.1993.tb05710.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Monfar M., Lemon K. P., Grammer T. C., Cheatham L., Chung J., Vlahos C. J., Blenis J. Activation of pp70/85 S6 kinases in interleukin-2-responsive lymphoid cells is mediated by phosphatidylinositol 3-kinase and inhibited by cyclic AMP. Mol Cell Biol. 1995 Jan;15(1):326–337. doi: 10.1128/mcb.15.1.326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. 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]
  39. Morice W. G., Brunn G. J., Wiederrecht G., Siekierka J. J., Abraham R. T. Rapamycin-induced inhibition of p34cdc2 kinase activation is associated with G1/S-phase growth arrest in T lymphocytes. J Biol Chem. 1993 Feb 15;268(5):3734–3738. [PubMed] [Google Scholar]
  40. Muslin A. J., Klippel A., Williams L. T. Phosphatidylinositol 3-kinase activity is important for progesterone-induced Xenopus oocyte maturation. Mol Cell Biol. 1993 Nov;13(11):6661–6666. doi: 10.1128/mcb.13.11.6661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Myers M. G., Jr, Grammer T. C., Wang L. M., Sun X. J., Pierce J. H., Blenis J., White M. F. Insulin receptor substrate-1 mediates phosphatidylinositol 3'-kinase and p70S6k signaling during insulin, insulin-like growth factor-1, and interleukin-4 stimulation. J Biol Chem. 1994 Nov 18;269(46):28783–28789. [PubMed] [Google Scholar]
  42. Nakamura Y., Russell S. M., Mess S. A., Friedmann M., Erdos M., Francois C., Jacques Y., Adelstein S., Leonard W. J. Heterodimerization of the IL-2 receptor beta- and gamma-chain cytoplasmic domains is required for signalling. Nature. 1994 May 26;369(6478):330–333. doi: 10.1038/369330a0. [DOI] [PubMed] [Google Scholar]
  43. Nakielny S., Cohen P., Wu J., Sturgill T. MAP kinase activator from insulin-stimulated skeletal muscle is a protein threonine/tyrosine kinase. EMBO J. 1992 Jun;11(6):2123–2129. doi: 10.1002/j.1460-2075.1992.tb05271.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Nelson B. H., Lord J. D., Greenberg P. D. Cytoplasmic domains of the interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation. Nature. 1994 May 26;369(6478):333–336. doi: 10.1038/369333a0. [DOI] [PubMed] [Google Scholar]
  45. Okada T., Kawano Y., Sakakibara T., Hazeki O., Ui M. Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin. J Biol Chem. 1994 Feb 4;269(5):3568–3573. [PubMed] [Google Scholar]
  46. Okada T., Sakuma L., Fukui Y., Hazeki O., Ui M. Blockage of chemotactic peptide-induced stimulation of neutrophils by wortmannin as a result of selective inhibition of phosphatidylinositol 3-kinase. J Biol Chem. 1994 Feb 4;269(5):3563–3567. [PubMed] [Google Scholar]
  47. Otani H., Siegel J. P., Erdos M., Gnarra J. R., Toledano M. B., Sharon M., Mostowski H., Feinberg M. B., Pierce J. H., Leonard W. J. Interleukin (IL)-2 and IL-3 induce distinct but overlapping responses in murine IL-3-dependent 32D cells transduced with human IL-2 receptor beta chain: involvement of tyrosine kinase(s) other than p56lck. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2789–2793. doi: 10.1073/pnas.89.7.2789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Posada J., Yew N., Ahn N. G., Vande Woude G. F., Cooper J. A. Mos stimulates MAP kinase in Xenopus oocytes and activates a MAP kinase kinase in vitro. Mol Cell Biol. 1993 Apr;13(4):2546–2553. doi: 10.1128/mcb.13.4.2546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Powis G., Bonjouklian R., Berggren M. M., Gallegos A., Abraham R., Ashendel C., Zalkow L., Matter W. F., Dodge J., Grindey G. Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res. 1994 May 1;54(9):2419–2423. [PubMed] [Google Scholar]
  50. Ravichandran K. S., Burakoff S. J. The adapter protein Shc interacts with the interleukin-2 (IL-2) receptor upon IL-2 stimulation. J Biol Chem. 1994 Jan 21;269(3):1599–1602. [PubMed] [Google Scholar]
  51. Remillard B., Petrillo R., Maslinski W., Tsudo M., Strom T. B., Cantley L., Varticovski L. Interleukin-2 receptor regulates activation of phosphatidylinositol 3-kinase. J Biol Chem. 1991 Aug 5;266(22):14167–14170. [PubMed] [Google Scholar]
  52. Robb R. J., Greene W. C. Internalization of interleukin 2 is mediated by the beta chain of the high-affinity interleukin 2 receptor. J Exp Med. 1987 Apr 1;165(4):1201–1206. doi: 10.1084/jem.165.4.1201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Rodriguez-Viciana P., Warne P. H., Dhand R., Vanhaesebroeck B., Gout I., Fry M. J., Waterfield M. D., Downward J. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature. 1994 Aug 18;370(6490):527–532. doi: 10.1038/370527a0. [DOI] [PubMed] [Google Scholar]
  54. Satoh T., Nakafuku M., Miyajima A., Kaziro Y. Involvement of ras p21 protein in signal-transduction pathways from interleukin 2, interleukin 3, and granulocyte/macrophage colony-stimulating factor, but not from interleukin 4. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3314–3318. doi: 10.1073/pnas.88.8.3314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Stokoe D., Macdonald S. G., Cadwallader K., Symons M., Hancock J. F. Activation of Raf as a result of recruitment to the plasma membrane. Science. 1994 Jun 3;264(5164):1463–1467. doi: 10.1126/science.7811320. [DOI] [PubMed] [Google Scholar]
  56. Sturgill T. W., Ray L. B., Anderson N. G., Erickson A. K. Purification of mitogen-activated protein kinase from epidermal growth factor-treated 3T3-L1 fibroblasts. Methods Enzymol. 1991;200:342–351. doi: 10.1016/0076-6879(91)00151-l. [DOI] [PubMed] [Google Scholar]
  57. Taniguchi T., Minami Y. The IL-2/IL-2 receptor system: a current overview. Cell. 1993 Apr 9;73(1):5–8. doi: 10.1016/0092-8674(93)90152-g. [DOI] [PubMed] [Google Scholar]
  58. Thelen M., Wymann M. P., Langen H. Wortmannin binds specifically to 1-phosphatidylinositol 3-kinase while inhibiting guanine nucleotide-binding protein-coupled receptor signaling in neutrophil leukocytes. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4960–4964. doi: 10.1073/pnas.91.11.4960. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Torigoe T., Saragovi H. U., Reed J. C. Interleukin 2 regulates the activity of the lyn protein-tyrosine kinase in a B-cell line. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2674–2678. doi: 10.1073/pnas.89.7.2674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Valius M., Kazlauskas A. Phospholipase C-gamma 1 and phosphatidylinositol 3 kinase are the downstream mediators of the PDGF receptor's mitogenic signal. Cell. 1993 Apr 23;73(2):321–334. doi: 10.1016/0092-8674(93)90232-f. [DOI] [PubMed] [Google Scholar]
  61. Vlahos C. J., Matter W. F., Hui K. Y., Brown R. F. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem. 1994 Feb 18;269(7):5241–5248. [PubMed] [Google Scholar]
  62. 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]
  63. Voss L. M., Abraham R. T., Rhodes K. H., Schoon R. A., Leibson P. J. Defective T-lymphocyte signal transduction and function in leukocyte adhesion deficiency. J Clin Immunol. 1991 Jul;11(4):175–183. doi: 10.1007/BF00917423. [DOI] [PubMed] [Google Scholar]
  64. 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]
  65. Witthuhn B. A., Silvennoinen O., Miura O., Lai K. S., Cwik C., Liu E. T., Ihle J. N. Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature. 1994 Jul 14;370(6485):153–157. doi: 10.1038/370153a0. [DOI] [PubMed] [Google Scholar]
  66. Wood K. W., Sarnecki C., Roberts T. M., Blenis J. ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK. Cell. 1992 Mar 20;68(6):1041–1050. doi: 10.1016/0092-8674(92)90076-o. [DOI] [PubMed] [Google Scholar]
  67. Yamauchi K., Holt K., Pessin J. E. Phosphatidylinositol 3-kinase functions upstream of Ras and Raf in mediating insulin stimulation of c-fos transcription. J Biol Chem. 1993 Jul 15;268(20):14597–14600. [PubMed] [Google Scholar]
  68. 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]
  69. Zheng C. F., Ohmichi M., Saltiel A. R., Guan K. L. Growth factor induced MEK activation is primarily mediated by an activator different from c-raf. Biochemistry. 1994 May 10;33(18):5595–5599. doi: 10.1021/bi00184a031. [DOI] [PubMed] [Google Scholar]
  70. Zhu X., Suen K. L., Barbacid M., Bolen J. B., Fargnoli J. Interleukin-2-induced tyrosine phosphorylation of Shc proteins correlates with factor-dependent T cell proliferation. J Biol Chem. 1994 Feb 25;269(8):5518–5522. [PubMed] [Google Scholar]

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