Skip to main content
NCBI home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1992 Nov;12(11):5078–5086. doi: 10.1128/mcb.12.11.5078

Raf-1 protein kinase is an integral component of the oncogenic signal cascade shared by epidermal growth factor and platelet-derived growth factor.

S Kizaka-Kondoh 1, K Sato 1, K Tamura 1, H Nojima 1, H Okayama 1
PMCID: PMC360441  PMID: 1406683

Abstract

Our recent studies with cell mutants indicate that a cascade shared by the epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) signals exists in NRK cells and mediates oncogenic signals induced by many oncogenes (A. Masuda, S. Kizaka-Kondoh, H. Miwatani, Y. Terada, H. Nojima, and H. Okayama, New Biol. 4:489-503, 1992). We have employed the antisense RNA technique to investigate possible involvement of Raf-1 kinase in this signal transduction cascade. NRK cell clones highly reduced in the Raf-1 production are generated by the expression of a c-raf-1 antisense RNA. They have no apparent growth defects and retain proper mitotic responses to growth factors but are refractory to transformation by EGF or PDGF plus transforming growth factor beta, v-erbB, v-fms, v-K-ras, v-mos, v-fos, v-src, simian virus 40 large T, and polyomavirus middle T but not by v-raf or adenovirus E1A. These results not only support our model for the oncogenic signal cascade but also lead to the conclusion that Raf-1 protein kinase is a downstream component of this oncogenic signal cascade shared by EGF and PDGF.

Full text

PDF
5078

Images in this article

5081Image
on p.5081
5082Image
on p.5082
5083Image
on p.5083
5084Image
on p.5084

Selected References

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

  1. Ambrosio L., Mahowald A. P., Perrimon N. Requirement of the Drosophila raf homologue for torso function. Nature. 1989 Nov 16;342(6247):288–291. doi: 10.1038/342288a0. [DOI] [PubMed] [Google Scholar]
  2. Anderson S. M., Klinken S. P., Hankins W. D. A murine recombinant retrovirus containing the src oncogene transforms erythroid precursor cells in vitro. Mol Cell Biol. 1985 Dec;5(12):3369–3375. doi: 10.1128/mcb.5.12.3369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. App H., Hazan R., Zilberstein A., Ullrich A., Schlessinger J., Rapp U. Epidermal growth factor (EGF) stimulates association and kinase activity of Raf-1 with the EGF receptor. Mol Cell Biol. 1991 Feb;11(2):913–919. doi: 10.1128/mcb.11.2.913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Assoian R. K. Biphasic effects of type beta transforming growth factor on epidermal growth factor receptors in NRK fibroblasts. Functional consequences for epidermal growth factor-stimulated mitosis. J Biol Chem. 1985 Aug 15;260(17):9613–9617. [PubMed] [Google Scholar]
  5. Baccarini M., Sabatini D. M., App H., Rapp U. R., Stanley E. R. Colony stimulating factor-1 (CSF-1) stimulates temperature dependent phosphorylation and activation of the RAF-1 proto-oncogene product. EMBO J. 1990 Nov;9(11):3649–3657. doi: 10.1002/j.1460-2075.1990.tb07576.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Blackshear P. J., Haupt D. M., App H., Rapp U. R. Insulin activates the Raf-1 protein kinase. J Biol Chem. 1990 Jul 25;265(21):12131–12134. [PubMed] [Google Scholar]
  7. Carroll M. P., Clark-Lewis I., Rapp U. R., May W. S. Interleukin-3 and granulocyte-macrophage colony-stimulating factor mediate rapid phosphorylation and activation of cytosolic c-raf. J Biol Chem. 1990 Nov 15;265(32):19812–19817. [PubMed] [Google Scholar]
  8. Chen C., Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. doi: 10.1128/mcb.7.8.2745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  10. Curran T., Franza B. R., Jr Fos and Jun: the AP-1 connection. Cell. 1988 Nov 4;55(3):395–397. doi: 10.1016/0092-8674(88)90024-4. [DOI] [PubMed] [Google Scholar]
  11. DeCaprio J. A., Ludlow J. W., Figge J., Shew J. Y., Huang C. M., Lee W. H., Marsilio E., Paucha E., Livingston D. M. SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell. 1988 Jul 15;54(2):275–283. doi: 10.1016/0092-8674(88)90559-4. [DOI] [PubMed] [Google Scholar]
  12. Donner L., Fedele L. A., Garon C. F., Anderson S. J., Sherr C. J. McDonough feline sarcoma virus: characterization of the molecularly cloned provirus and its feline oncogene (v-fms). J Virol. 1982 Feb;41(2):489–500. doi: 10.1128/jvi.41.2.489-500.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Donoghue D. J., Anderson C., Hunter T., Kaplan P. L. Transmission of the polyoma virus middle T gene as the oncogene of a murine retrovirus. Nature. 1984 Apr 19;308(5961):748–750. doi: 10.1038/308748a0. [DOI] [PubMed] [Google Scholar]
  14. Ellis C., Moran M., McCormick F., Pawson T. Phosphorylation of GAP and GAP-associated proteins by transforming and mitogenic tyrosine kinases. Nature. 1990 Jan 25;343(6256):377–381. doi: 10.1038/343377a0. [DOI] [PubMed] [Google Scholar]
  15. Gluzman Y., Sambrook J. F., Frisque R. J. Expression of early genes of origin-defective mutants of simian virus 40. Proc Natl Acad Sci U S A. 1980 Jul;77(7):3898–3902. doi: 10.1073/pnas.77.7.3898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gunning P., Leavitt J., Muscat G., Ng S. Y., Kedes L. A human beta-actin expression vector system directs high-level accumulation of antisense transcripts. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4831–4835. doi: 10.1073/pnas.84.14.4831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Heidecker G., Huleihel M., Cleveland J. L., Kolch W., Beck T. W., Lloyd P., Pawson T., Rapp U. R. Mutational activation of c-raf-1 and definition of the minimal transforming sequence. Mol Cell Biol. 1990 Jun;10(6):2503–2512. doi: 10.1128/mcb.10.6.2503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kaplan D. R., Morrison D. K., Wong G., McCormick F., Williams L. T. PDGF beta-receptor stimulates tyrosine phosphorylation of GAP and association of GAP with a signaling complex. Cell. 1990 Apr 6;61(1):125–133. doi: 10.1016/0092-8674(90)90220-9. [DOI] [PubMed] [Google Scholar]
  19. Kizaka S., Hakura A. A cell mutant that exhibits temperature-dependent sensitivity to transformation by various oncogenes. Mol Cell Biol. 1989 Dec;9(12):5669–5675. doi: 10.1128/mcb.9.12.5669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kolch W., Heidecker G., Lloyd P., Rapp U. R. Raf-1 protein kinase is required for growth of induced NIH/3T3 cells. Nature. 1991 Jan 31;349(6308):426–428. doi: 10.1038/349426a0. [DOI] [PubMed] [Google Scholar]
  21. Kovacina K. S., Yonezawa K., Brautigan D. L., Tonks N. K., Rapp U. R., Roth R. A. Insulin activates the kinase activity of the Raf-1 proto-oncogene by increasing its serine phosphorylation. J Biol Chem. 1990 Jul 25;265(21):12115–12118. [PubMed] [Google Scholar]
  22. Margolis B., Rhee S. G., Felder S., Mervic M., Lyall R., Levitzki A., Ullrich A., Zilberstein A., Schlessinger J. EGF induces tyrosine phosphorylation of phospholipase C-II: a potential mechanism for EGF receptor signaling. Cell. 1989 Jun 30;57(7):1101–1107. doi: 10.1016/0092-8674(89)90047-0. [DOI] [PubMed] [Google Scholar]
  23. Molloy C. J., Bottaro D. P., Fleming T. P., Marshall M. S., Gibbs J. B., Aaronson S. A. PDGF induction of tyrosine phosphorylation of GTPase activating protein. Nature. 1989 Dec 7;342(6250):711–714. doi: 10.1038/342711a0. [DOI] [PubMed] [Google Scholar]
  24. Morrison D. K., Kaplan D. R., Rapp U., Roberts T. M. Signal transduction from membrane to cytoplasm: growth factors and membrane-bound oncogene products increase Raf-1 phosphorylation and associated protein kinase activity. Proc Natl Acad Sci U S A. 1988 Dec;85(23):8855–8859. doi: 10.1073/pnas.85.23.8855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Nakajima T., Nakamura T., Tsunoda S., Nakada S., Oda K. E1A-responsive elements for repression of rat fibronectin gene transcription. Mol Cell Biol. 1992 Jun;12(6):2837–2846. doi: 10.1128/mcb.12.6.2837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rapp U. R., Goldsborough M. D., Mark G. E., Bonner T. I., Groffen J., Reynolds F. H., Jr, Stephenson J. R. Structure and biological activity of v-raf, a unique oncogene transduced by a retrovirus. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4218–4222. doi: 10.1073/pnas.80.14.4218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Rapp U. R., Heidecker G., Huleihel M., Cleveland J. L., Choi W. C., Pawson T., Ihle J. N., Anderson W. B. raf family serine/threonine protein kinases in mitogen signal transduction. Cold Spring Harb Symp Quant Biol. 1988;53(Pt 1):173–184. doi: 10.1101/sqb.1988.053.01.023. [DOI] [PubMed] [Google Scholar]
  28. Schultz A. M., Copeland T. D., Mark G. E., Rapp U. R., Oroszlan S. Detection of the myristylated gag-raf transforming protein with raf-specific antipeptide sera. Virology. 1985 Oct 15;146(1):78–89. doi: 10.1016/0042-6822(85)90054-6. [DOI] [PubMed] [Google Scholar]
  29. Setoyama C., Frunzio R., Liau G., Mudryj M., de Crombrugghe B. Transcriptional activation encoded by the v-fos gene. Proc Natl Acad Sci U S A. 1986 May;83(10):3213–3217. doi: 10.1073/pnas.83.10.3213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Siegel J. N., Klausner R. D., Rapp U. R., Samelson L. E. T cell antigen receptor engagement stimulates c-raf phosphorylation and induces c-raf-associated kinase activity via a protein kinase C-dependent pathway. J Biol Chem. 1990 Oct 25;265(30):18472–18480. [PubMed] [Google Scholar]
  31. Stanton V. P., Jr, Nichols D. W., Laudano A. P., Cooper G. M. Definition of the human raf amino-terminal regulatory region by deletion mutagenesis. Mol Cell Biol. 1989 Feb;9(2):639–647. doi: 10.1128/mcb.9.2.639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Storm S. M., Cleveland J. L., Rapp U. R. Expression of raf family proto-oncogenes in normal mouse tissues. Oncogene. 1990 Mar;5(3):345–351. [PubMed] [Google Scholar]
  33. Turner B., Rapp U., App H., Greene M., Dobashi K., Reed J. Interleukin 2 induces tyrosine phosphorylation and activation of p72-74 Raf-1 kinase in a T-cell line. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1227–1231. doi: 10.1073/pnas.88.4.1227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Whyte P., Buchkovich K. J., Horowitz J. M., Friend S. H., Raybuck M., Weinberg R. A., Harlow E. Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product. Nature. 1988 Jul 14;334(6178):124–129. doi: 10.1038/334124a0. [DOI] [PubMed] [Google Scholar]
  35. Zinn K., DiMaio D., Maniatis T. Identification of two distinct regulatory regions adjacent to the human beta-interferon gene. Cell. 1983 Oct;34(3):865–879. doi: 10.1016/0092-8674(83)90544-5. [DOI] [PubMed] [Google Scholar]

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

RESOURCES