Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Feb 28;92(5):1614–1618. doi: 10.1073/pnas.92.5.1614

Tumor necrosis factor alpha rapidly activates the mitogen-activated protein kinase (MAPK) cascade in a MAPK kinase kinase-dependent, c-Raf-1-independent fashion in mouse macrophages.

B W Winston 1, C A Lange-Carter 1, A M Gardner 1, G L Johnson 1, D W Riches 1
PMCID: PMC42570  PMID: 7878028

Abstract

Tumor necrosis factor alpha (TNF alpha) is bound by two cell surface receptors, CD120a (p55) and CD120b (p75), that belong to the TNF/nerve growth factor receptor family and whose signaling is initiated by receptor multimerization in the plane of the plasma membrane. The initial signaling events activated by receptor crosslinking are unknown, although activation of the mitogen-activated protein kinase (MAPK) cascade occurs shortly after ligand binding to CD120a. In this study, we investigated the upstream kinases that mediate the activation of the 42-kDa MAPK p42mapk/erk2 following crosslinking of CD120a in mouse macrophages. Exposure of mouse macrophages to TNF alpha stimulated a time-dependent increase in the activity of MAPK/ERK kinase (MEK) that temporally preceded peak activation of p42mapk/erk2. MEKs, dual-specificity threonine/tyrosine kinases, act as a convergence point for several signaling pathways including Ras/Raf, MEK kinase (MEKK), and Mos. Incubation of macrophages with TNF alpha was found to transiently stimulate a MEKK that peaked in activity within 30 sec of exposure and progressively declined toward basal levels by 5 min. By contrast, under these conditions, activation of either c-Raf-1 or Raf-B was not detected. These data suggest that the activation of the MAPK cascade in response to TNF alpha is mediated by the sequential activation of a MEKK and a MEK in a c-Raf-1- and Raf-B-independent fashion.

Full text

PDF
1614

Images in this article

1616Fig. 1
on p.1616
1616Fig. 2
on p.1616
1617Fig. 3
on p.1617
1617Fig. 4
on p.1617

Selected References

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

  1. 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]
  2. Chao T. S., Foster D. A., Rapp U. R., Rosner M. R. Differential Raf requirement for activation of mitogen-activated protein kinase by growth factors, phorbol esters, and calcium. J Biol Chem. 1994 Mar 11;269(10):7337–7341. [PubMed] [Google Scholar]
  3. Crews C. M., Erikson R. L. Extracellular signals and reversible protein phosphorylation: what to Mek of it all. Cell. 1993 Jul 30;74(2):215–217. doi: 10.1016/0092-8674(93)90411-i. [DOI] [PubMed] [Google Scholar]
  4. Ding A. H., Nathan C. F., Stuehr D. J. Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J Immunol. 1988 Oct 1;141(7):2407–2412. [PubMed] [Google Scholar]
  5. Gardner A. M., Vaillancourt R. R., Johnson G. L. Activation of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase by G protein and tyrosine kinase oncoproteins. J Biol Chem. 1993 Aug 25;268(24):17896–17901. [PubMed] [Google Scholar]
  6. Gardner A. M., Vaillancourt R. R., Lange-Carter C. A., Johnson G. L. MEK-1 phosphorylation by MEK kinase, Raf, and mitogen-activated protein kinase: analysis of phosphopeptides and regulation of activity. Mol Biol Cell. 1994 Feb;5(2):193–201. doi: 10.1091/mbc.5.2.193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Haystead C. M., Gregory P., Shirazi A., Fadden P., Mosse C., Dent P., Haystead T. A. Insulin activates a novel adipocyte mitogen-activated protein kinase kinase kinase that shows rapid phasic kinetics and is distinct from c-Raf. J Biol Chem. 1994 Apr 29;269(17):12804–12808. [PubMed] [Google Scholar]
  8. Heasley L. E., Johnson G. L. The beta-PDGF receptor induces neuronal differentiation of PC12 cells. Mol Biol Cell. 1992 May;3(5):545–553. doi: 10.1091/mbc.3.5.545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hori K., Mihich E., Ehrke M. J. Role of tumor necrosis factor and interleukin 1 in gamma-interferon-promoted activation of mouse tumoricidal macrophages. Cancer Res. 1989 May 15;49(10):2606–2614. [PubMed] [Google Scholar]
  10. 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]
  11. Kyriakis J. M., App H., Zhang X. F., Banerjee P., Brautigan D. L., Rapp U. R., Avruch J. Raf-1 activates MAP kinase-kinase. Nature. 1992 Jul 30;358(6385):417–421. doi: 10.1038/358417a0. [DOI] [PubMed] [Google Scholar]
  12. Kyriakis J. M., Banerjee P., Nikolakaki E., Dai T., Rubie E. A., Ahmad M. F., Avruch J., Woodgett J. R. The stress-activated protein kinase subfamily of c-Jun kinases. Nature. 1994 May 12;369(6476):156–160. doi: 10.1038/369156a0. [DOI] [PubMed] [Google Scholar]
  13. Lake F. R., Noble P. W., Henson P. M., Riches D. W. Functional switching of macrophage responses to tumor necrosis factor-alpha (TNF alpha) by interferons. Implications for the pleiotropic activities of TNF alpha. J Clin Invest. 1994 Apr;93(4):1661–1669. doi: 10.1172/JCI117148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. 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]
  16. Lin L. L., Wartmann M., Lin A. Y., Knopf J. L., Seth A., Davis R. J. cPLA2 is phosphorylated and activated by MAP kinase. Cell. 1993 Jan 29;72(2):269–278. doi: 10.1016/0092-8674(93)90666-e. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Müller M., Briscoe J., Laxton C., Guschin D., Ziemiecki A., Silvennoinen O., Harpur A. G., Barbieri G., Witthuhn B. A., Schindler C. The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature. 1993 Nov 11;366(6451):129–135. doi: 10.1038/366129a0. [DOI] [PubMed] [Google Scholar]
  19. Noble P. W., Lake F. R., Henson P. M., Riches D. W. Hyaluronate activation of CD44 induces insulin-like growth factor-1 expression by a tumor necrosis factor-alpha-dependent mechanism in murine macrophages. J Clin Invest. 1993 Jun;91(6):2368–2377. doi: 10.1172/JCI116469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Payne D. M., Rossomando A. J., Martino P., Erickson A. K., Her J. H., Shabanowitz J., Hunt D. F., Weber M. J., Sturgill T. W. Identification of the regulatory phosphorylation sites in pp42/mitogen-activated protein kinase (MAP kinase). EMBO J. 1991 Apr;10(4):885–892. doi: 10.1002/j.1460-2075.1991.tb08021.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. Raines M. A., Kolesnick R. N., Golde D. W. Sphingomyelinase and ceramide activate mitogen-activated protein kinase in myeloid HL-60 cells. J Biol Chem. 1993 Jul 15;268(20):14572–14575. [PubMed] [Google Scholar]
  23. Riches D. W., Underwood G. A. Expression of interferon-beta during the triggering phase of macrophage cytocidal activation. Evidence for an autocrine/paracrine role in the regulation of this state. J Biol Chem. 1991 Dec 25;266(36):24785–24792. [PubMed] [Google Scholar]
  24. Seth A., Gonzalez F. A., Gupta S., Raden D. L., Davis R. J. Signal transduction within the nucleus by mitogen-activated protein kinase. J Biol Chem. 1992 Dec 5;267(34):24796–24804. [PubMed] [Google Scholar]
  25. Stephens R. M., Sithanandam G., Copeland T. D., Kaplan D. R., Rapp U. R., Morrison D. K. 95-kilodalton B-Raf serine/threonine kinase: identification of the protein and its major autophosphorylation site. Mol Cell Biol. 1992 Sep;12(9):3733–3742. doi: 10.1128/mcb.12.9.3733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. 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]
  27. 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]
  28. Takishima K., Griswold-Prenner I., Ingebritsen T., Rosner M. R. Epidermal growth factor (EGF) receptor T669 peptide kinase from 3T3-L1 cells is an EGF-stimulated "MAP" kinase. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2520–2524. doi: 10.1073/pnas.88.6.2520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Tartaglia L. A., Ayres T. M., Wong G. H., Goeddel D. V. A novel domain within the 55 kd TNF receptor signals cell death. Cell. 1993 Sep 10;74(5):845–853. doi: 10.1016/0092-8674(93)90464-2. [DOI] [PubMed] [Google Scholar]
  30. Tartaglia L. A., Goeddel D. V. Tumor necrosis factor receptor signaling. A dominant negative mutation suppresses the activation of the 55-kDa tumor necrosis factor receptor. J Biol Chem. 1992 Mar 5;267(7):4304–4307. [PubMed] [Google Scholar]
  31. Tartaglia L. A., Goeddel D. V. Two TNF receptors. Immunol Today. 1992 May;13(5):151–153. doi: 10.1016/0167-5699(92)90116-O. [DOI] [PubMed] [Google Scholar]
  32. Tordai A., Franklin R. A., Patel H., Gardner A. M., Johnson G. L., Gelfand E. W. Cross-linking of surface IgM stimulates the Ras/Raf-1/MEK/MAPK cascade in human B lymphocytes. J Biol Chem. 1994 Mar 11;269(10):7538–7543. [PubMed] [Google Scholar]
  33. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Vietor I., Schwenger P., Li W., Schlessinger J., Vilcek J. Tumor necrosis factor-induced activation and increased tyrosine phosphorylation of mitogen-activated protein (MAP) kinase in human fibroblasts. J Biol Chem. 1993 Sep 5;268(25):18994–18999. [PubMed] [Google Scholar]
  35. Williams N. G., Paradis H., Agarwal S., Charest D. L., Pelech S. L., Roberts T. M. Raf-1 and p21v-ras cooperate in the activation of mitogen-activated protein kinase. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5772–5776. doi: 10.1073/pnas.90.12.5772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wu J., Harrison J. K., Dent P., Lynch K. R., Weber M. J., Sturgill T. W. Identification and characterization of a new mammalian mitogen-activated protein kinase kinase, MKK2. Mol Cell Biol. 1993 Aug;13(8):4539–4548. doi: 10.1128/mcb.13.8.4539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Zheng C. F., Guan K. L. Properties of MEKs, the kinases that phosphorylate and activate the extracellular signal-regulated kinases. J Biol Chem. 1993 Nov 15;268(32):23933–23939. [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES