Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1996 Feb 15;15(4):817–826.

Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase.

A Salmeron 1, T B Ahmad 1, G W Carlile 1, D Pappin 1, R P Narsimhan 1, S C Ley 1
PMCID: PMC450280  PMID: 8631303

Abstract

The Tpl-2 protein serine/threonine kinase was originally identified, in a C-terminally deleted form, as the product of an oncogene associated with the progression of Moloney murine leukemia virus-induced T cell lymphomas in rats. The kinase domain of Tpl-2 is homologous to the Saccharomyces cerevisiae gene product, STE11, which encodes a MAP kinase kinase kinase. This suggested that Tpl-2 might have a similar activity. Consistent with this hypothesis, immunoprecipitated Tpl-2 and Tpl-2deltaC (a C-terminally truncated mutant) phosphorylated and activated recombinant fusion proteins of the mammalian MAP kinase kinases, MEK-1 and SEK-1, in vitro. Furthermore, transfection of Tpl-2 into COS-1 cells or Jurkat T cells. markedly activated the MAP kinases, ERK-1 and SAP kinase (JNK), which are substrates for MEK-1 and SEK-1, respectively. Tpl-2, therefore, is a MAP kinase kinase kinase which can activate two MAP kinase pathways. After Raf and Mos, Tpl-2 is the third serine/threonine oncoprotein kinase that has been shown to function as a direct activator of MEK-1.

Full text

PDF
820

Images in this article

818Image
on p.818
819Image
on p.819
820Image
on p.820
821Image
on p.821
822Image
on p.822
822Image
on p.822
823Image
on p.823

Selected References

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

  1. Alessi D. R., Saito Y., Campbell D. G., Cohen P., Sithanandam G., Rapp U., Ashworth A., Marshall C. J., Cowley S. Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1. EMBO J. 1994 Apr 1;13(7):1610–1619. doi: 10.1002/j.1460-2075.1994.tb06424.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alvarez E., Northwood I. C., Gonzalez F. A., Latour D. A., Seth A., Abate C., Curran T., Davis R. J. Pro-Leu-Ser/Thr-Pro is a consensus primary sequence for substrate protein phosphorylation. Characterization of the phosphorylation of c-myc and c-jun proteins by an epidermal growth factor receptor threonine 669 protein kinase. J Biol Chem. 1991 Aug 15;266(23):15277–15285. [PubMed] [Google Scholar]
  3. Aoki M., Hamada F., Sugimoto T., Sumida S., Akiyama T., Toyoshima K. The human cot proto-oncogene encodes two protein serine/threonine kinases with different transforming activities by alternative initiation of translation. J Biol Chem. 1993 Oct 25;268(30):22723–22732. [PubMed] [Google Scholar]
  4. Cano E., Mahadevan L. C. Parallel signal processing among mammalian MAPKs. Trends Biochem Sci. 1995 Mar;20(3):117–122. doi: 10.1016/s0968-0004(00)88978-1. [DOI] [PubMed] [Google Scholar]
  5. Chan A. M., Chedid M., McGovern E. S., Popescu N. C., Miki T., Aaronson S. A. Expression cDNA cloning of a serine kinase transforming gene. Oncogene. 1993 May;8(5):1329–1333. [PubMed] [Google Scholar]
  6. Coso O. A., Chiariello M., Kalinec G., Kyriakis J. M., Woodgett J., Gutkind J. S. Transforming G protein-coupled receptors potently activate JNK (SAPK). Evidence for a divergence from the tyrosine kinase signaling pathway. J Biol Chem. 1995 Mar 10;270(10):5620–5624. doi: 10.1074/jbc.270.10.5620. [DOI] [PubMed] [Google Scholar]
  7. Cowley S., Paterson H., Kemp P., Marshall C. J. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell. 1994 Jun 17;77(6):841–852. doi: 10.1016/0092-8674(94)90133-3. [DOI] [PubMed] [Google Scholar]
  8. Dent P., Haser W., Haystead T. A., Vincent L. A., Roberts T. M., Sturgill T. W. Activation of mitogen-activated protein kinase kinase by v-Raf in NIH 3T3 cells and in vitro. Science. 1992 Sep 4;257(5075):1404–1407. doi: 10.1126/science.1326789. [DOI] [PubMed] [Google Scholar]
  9. Dérijard B., Hibi M., Wu I. H., Barrett T., Su B., Deng T., Karin M., Davis R. J. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell. 1994 Mar 25;76(6):1025–1037. doi: 10.1016/0092-8674(94)90380-8. [DOI] [PubMed] [Google Scholar]
  10. Dérijard B., Raingeaud J., Barrett T., Wu I. H., Han J., Ulevitch R. J., Davis R. J. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995 Feb 3;267(5198):682–685. doi: 10.1126/science.7839144. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Errede B., Levin D. E. A conserved kinase cascade for MAP kinase activation in yeast. Curr Opin Cell Biol. 1993 Apr;5(2):254–260. doi: 10.1016/0955-0674(93)90112-4. [DOI] [PubMed] [Google Scholar]
  13. Evan G. I., Lewis G. K., Ramsay G., Bishop J. M. Isolation of monoclonal antibodies specific for human c-myc proto-oncogene product. Mol Cell Biol. 1985 Dec;5(12):3610–3616. doi: 10.1128/mcb.5.12.3610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Field J., Nikawa J., Broek D., MacDonald B., Rodgers L., Wilson I. A., Lerner R. A., Wigler M. Purification of a RAS-responsive adenylyl cyclase complex from Saccharomyces cerevisiae by use of an epitope addition method. Mol Cell Biol. 1988 May;8(5):2159–2165. doi: 10.1128/mcb.8.5.2159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gupta S., Campbell D., Dérijard B., Davis R. J. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science. 1995 Jan 20;267(5196):389–393. doi: 10.1126/science.7824938. [DOI] [PubMed] [Google Scholar]
  16. Han J., Lee J. D., Bibbs L., Ulevitch R. J. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science. 1994 Aug 5;265(5173):808–811. doi: 10.1126/science.7914033. [DOI] [PubMed] [Google Scholar]
  17. Herskowitz I. MAP kinase pathways in yeast: for mating and more. Cell. 1995 Jan 27;80(2):187–197. doi: 10.1016/0092-8674(95)90402-6. [DOI] [PubMed] [Google Scholar]
  18. Hibi M., Lin A., Smeal T., Minden A., Karin M. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 1993 Nov;7(11):2135–2148. doi: 10.1101/gad.7.11.2135. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. 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]
  21. Izquierdo M., Bowden S., Cantrell D. The role of Raf-1 in the regulation of extracellular signal-regulated kinase 2 by the T cell antigen receptor. J Exp Med. 1994 Jul 1;180(1):401–406. doi: 10.1084/jem.180.1.401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kayne P. S., Sternberg P. W. Ras pathways in Caenorhabditis elegans. Curr Opin Genet Dev. 1995 Feb;5(1):38–43. doi: 10.1016/s0959-437x(95)90051-9. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. 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]
  25. 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]
  26. Lee J. C., Laydon J. T., McDonnell P. C., Gallagher T. F., Kumar S., Green D., McNulty D., Blumenthal M. J., Heys J. R., Landvatter S. W. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994 Dec 22;372(6508):739–746. doi: 10.1038/372739a0. [DOI] [PubMed] [Google Scholar]
  27. Lee K. S., Levin D. E. Dominant mutations in a gene encoding a putative protein kinase (BCK1) bypass the requirement for a Saccharomyces cerevisiae protein kinase C homolog. Mol Cell Biol. 1992 Jan;12(1):172–182. doi: 10.1128/mcb.12.1.172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Leevers S. J., Marshall C. J. Activation of extracellular signal-regulated kinase, ERK2, by p21ras oncoprotein. EMBO J. 1992 Feb;11(2):569–574. doi: 10.1002/j.1460-2075.1992.tb05088.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. 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]
  30. Lenormand P., Sardet C., Pagès G., L'Allemain G., Brunet A., Pouysségur J. Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts. J Cell Biol. 1993 Sep;122(5):1079–1088. doi: 10.1083/jcb.122.5.1079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lin A., Minden A., Martinetto H., Claret F. X., Lange-Carter C., Mercurio F., Johnson G. L., Karin M. Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science. 1995 Apr 14;268(5208):286–290. doi: 10.1126/science.7716521. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. Livingstone C., Patel G., Jones N. ATF-2 contains a phosphorylation-dependent transcriptional activation domain. EMBO J. 1995 Apr 18;14(8):1785–1797. doi: 10.1002/j.1460-2075.1995.tb07167.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Makris A., Patriotis C., Bear S. E., Tsichlis P. N. Genomic organization and expression of Tpl-2 in normal cells and Moloney murine leukemia virus-induced rat T-cell lymphomas: activation by provirus insertion. J Virol. 1993 Jul;67(7):4283–4289. doi: 10.1128/jvi.67.7.4283-4289.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Mansour S. J., Matten W. T., Hermann A. S., Candia J. M., Rong S., Fukasawa K., Vande Woude G. F., Ahn N. G. Transformation of mammalian cells by constitutively active MAP kinase kinase. Science. 1994 Aug 12;265(5174):966–970. doi: 10.1126/science.8052857. [DOI] [PubMed] [Google Scholar]
  36. Marais R., Light Y., Paterson H. F., Marshall C. J. Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. EMBO J. 1995 Jul 3;14(13):3136–3145. doi: 10.1002/j.1460-2075.1995.tb07316.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. 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]
  38. Marshall C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995 Jan 27;80(2):179–185. doi: 10.1016/0092-8674(95)90401-8. [DOI] [PubMed] [Google Scholar]
  39. Minden A., Lin A., McMahon M., Lange-Carter C., Dérijard B., Davis R. J., Johnson G. L., Karin M. Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. Science. 1994 Dec 9;266(5191):1719–1723. doi: 10.1126/science.7992057. [DOI] [PubMed] [Google Scholar]
  40. Miyoshi J., Higashi T., Mukai H., Ohuchi T., Kakunaga T. Structure and transforming potential of the human cot oncogene encoding a putative protein kinase. Mol Cell Biol. 1991 Aug;11(8):4088–4096. doi: 10.1128/mcb.11.8.4088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Nebreda A. R., Hill C., Gomez N., Cohen P., Hunt T. The protein kinase mos activates MAP kinase kinase in vitro and stimulates the MAP kinase pathway in mammalian somatic cells in vivo. FEBS Lett. 1993 Oct 25;333(1-2):183–187. doi: 10.1016/0014-5793(93)80401-f. [DOI] [PubMed] [Google Scholar]
  42. Ohara R., Miyoshi J., Aoki M., Toyoshima K. The murine cot proto-oncogene: genome structure and tissue-specific expression. Jpn J Cancer Res. 1993 May;84(5):518–525. doi: 10.1111/j.1349-7006.1993.tb00170.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Okazaki K., Sagata N. MAP kinase activation is essential for oncogenic transformation of NIH3T3 cells by Mos. Oncogene. 1995 Mar 16;10(6):1149–1157. [PubMed] [Google Scholar]
  44. Owaki H., Varma R., Gillis B., Bruder J. T., Rapp U. R., Davis L. S., Geppert T. D. Raf-1 is required for T cell IL2 production. EMBO J. 1993 Nov;12(11):4367–4373. doi: 10.1002/j.1460-2075.1993.tb06121.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Patriotis C., Makris A., Bear S. E., Tsichlis P. N. Tumor progression locus 2 (Tpl-2) encodes a protein kinase involved in the progression of rodent T-cell lymphomas and in T-cell activation. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2251–2255. doi: 10.1073/pnas.90.6.2251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Patriotis C., Makris A., Chernoff J., Tsichlis P. N. Tpl-2 acts in concert with Ras and Raf-1 to activate mitogen-activated protein kinase. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9755–9759. doi: 10.1073/pnas.91.21.9755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Rhodes N., Connell L., Errede B. STE11 is a protein kinase required for cell-type-specific transcription and signal transduction in yeast. Genes Dev. 1990 Nov;4(11):1862–1874. doi: 10.1101/gad.4.11.1862. [DOI] [PubMed] [Google Scholar]
  48. Robb R. J., Munck A., Smith K. A. T cell growth factor receptors. Quantitation, specificity, and biological relevance. J Exp Med. 1981 Nov 1;154(5):1455–1474. doi: 10.1084/jem.154.5.1455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Robbins D. J., Zhen E., Owaki H., Vanderbilt C. A., Ebert D., Geppert T. D., Cobb M. H. Regulation and properties of extracellular signal-regulated protein kinases 1 and 2 in vitro. J Biol Chem. 1993 Mar 5;268(7):5097–5106. [PubMed] [Google Scholar]
  50. Rouse J., Cohen P., Trigon S., Morange M., Alonso-Llamazares A., Zamanillo D., Hunt T., Nebreda A. R. A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell. 1994 Sep 23;78(6):1027–1037. doi: 10.1016/0092-8674(94)90277-1. [DOI] [PubMed] [Google Scholar]
  51. Schaap D., van der Wal J., Howe L. R., Marshall C. J., van Blitterswijk W. J. A dominant-negative mutant of raf blocks mitogen-activated protein kinase activation by growth factors and oncogenic p21ras. J Biol Chem. 1993 Sep 25;268(27):20232–20236. [PubMed] [Google Scholar]
  52. Schneider C., Newman R. A., Sutherland D. R., Asser U., Greaves M. F. A one-step purification of membrane proteins using a high efficiency immunomatrix. J Biol Chem. 1982 Sep 25;257(18):10766–10769. [PubMed] [Google Scholar]
  53. Stokoe D., Campbell D. G., Nakielny S., Hidaka H., Leevers S. J., Marshall C., Cohen P. MAPKAP kinase-2; a novel protein kinase activated by mitogen-activated protein kinase. EMBO J. 1992 Nov;11(11):3985–3994. doi: 10.1002/j.1460-2075.1992.tb05492.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Su B., Jacinto E., Hibi M., Kallunki T., Karin M., Ben-Neriah Y. JNK is involved in signal integration during costimulation of T lymphocytes. Cell. 1994 Jun 3;77(5):727–736. doi: 10.1016/0092-8674(94)90056-6. [DOI] [PubMed] [Google Scholar]
  55. Sánchez I., Hughes R. T., Mayer B. J., Yee K., Woodgett J. R., Avruch J., Kyriakis J. M., Zon L. I. Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun. Nature. 1994 Dec 22;372(6508):794–798. doi: 10.1038/372794a0. [DOI] [PubMed] [Google Scholar]
  56. Troppmair J., Bruder J. T., Munoz H., Lloyd P. A., Kyriakis J., Banerjee P., Avruch J., Rapp U. R. Mitogen-activated protein kinase/extracellular signal-regulated protein kinase activation by oncogenes, serum, and 12-O-tetradecanoylphorbol-13-acetate requires Raf and is necessary for transformation. J Biol Chem. 1994 Mar 4;269(9):7030–7035. [PubMed] [Google Scholar]
  57. Wang Y., Xu H. P., Riggs M., Rodgers L., Wigler M. byr2, a Schizosaccharomyces pombe gene encoding a protein kinase capable of partial suppression of the ras1 mutant phenotype. Mol Cell Biol. 1991 Jul;11(7):3554–3563. doi: 10.1128/mcb.11.7.3554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Wassarman D. A., Therrien M., Rubin G. M. The Ras signaling pathway in Drosophila. Curr Opin Genet Dev. 1995 Feb;5(1):44–50. doi: 10.1016/s0959-437x(95)90052-7. [DOI] [PubMed] [Google Scholar]
  59. Yan M., Dai T., Deak J. C., Kyriakis J. M., Zon L. I., Woodgett J. R., Templeton D. J. Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1. Nature. 1994 Dec 22;372(6508):798–800. doi: 10.1038/372798a0. [DOI] [PubMed] [Google Scholar]
  60. Zheng C. F., Guan K. L. Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues. EMBO J. 1994 Mar 1;13(5):1123–1131. doi: 10.1002/j.1460-2075.1994.tb06361.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES