MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates (original) (raw)

Abstract

We have developed a novel expression screening method for identifying protein kinase substrates. In this method, a lambda phage cDNA expression library is screened by in situ, solid-phase phosphorylation using purified protein kinase and [gamma-32P]ATP. Screening a HeLa cDNA library with ERK1 MAP kinase yielded cDNAs of previously characterized ERK substrates, c-Myc and p90RSK, demonstrating the utility of this method for identifying physiological protein kinase substrates. A novel clone isolated in this screen, designated MNK1, encodes a protein-serine/threonine kinase, which is most similar to MAP kinase-activated protein kinase 2 (MAPKAP-K2), 3pK/MAPKAP-K3 and p90RSK. Bacterially expressed MNK1 was phosphorylated and activated in vitro by ERK1 and p38 MAP kinases but not by JNK/SAPK. Further, MNK1 was activated upon stimulation of HeLa cells with 12-O-tetradecanoylphorbol-13-acetate, fetal calf serum, anisomycin, UV irradiation, tumor necrosis factor-alpha, interleukin-1beta, or osmotic shock, and the activation by these stimuli was differentially inhibited by the MEK inhibitor PD098059 or the p38 MAP kinase inhibitor SB202190. Together, these results indicate that MNK1 is a novel class of protein kinase that is activated through both the ERK and p38 MAP kinase signaling pathways.

Full Text

The Full Text of this article is available as a PDF (812.7 KB).

Selected References

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

  1. Albright C. F., Giddings B. W., Liu J., Vito M., Weinberg R. A. Characterization of a guanine nucleotide dissociation stimulator for a ras-related GTPase. EMBO J. 1993 Jan;12(1):339–347. doi: 10.1002/j.1460-2075.1993.tb05662.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alessi D. R., Cuenda A., Cohen P., Dudley D. T., Saltiel A. R. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem. 1995 Nov 17;270(46):27489–27494. doi: 10.1074/jbc.270.46.27489. [DOI] [PubMed] [Google Scholar]
  3. Ben-Levy R., Leighton I. A., Doza Y. N., Attwood P., Morrice N., Marshall C. J., Cohen P. Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2. EMBO J. 1995 Dec 1;14(23):5920–5930. doi: 10.1002/j.1460-2075.1995.tb00280.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Brunet A., Pouysségur J. Identification of MAP kinase domains by redirecting stress signals into growth factor responses. Science. 1996 Jun 14;272(5268):1652–1655. doi: 10.1126/science.272.5268.1652. [DOI] [PubMed] [Google Scholar]
  6. Bunone G., Briand P. A., Miksicek R. J., Picard D. Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J. 1996 May 1;15(9):2174–2183. [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. Cooper J. A. MAP kinase pathways. Straight and narrow or tortuous and intersecting? Curr Biol. 1994 Dec 1;4(12):1118–1121. doi: 10.1016/s0960-9822(00)00251-7. [DOI] [PubMed] [Google Scholar]
  9. Davis R. J. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem. 1993 Jul 15;268(20):14553–14556. [PubMed] [Google Scholar]
  10. Engel K., Plath K., Gaestel M. The MAP kinase-activated protein kinase 2 contains a proline-rich SH3-binding domain. FEBS Lett. 1993 Dec 20;336(1):143–147. doi: 10.1016/0014-5793(93)81628-d. [DOI] [PubMed] [Google Scholar]
  11. Fazioli F., Minichiello L., Matoska V., Castagnino P., Miki T., Wong W. T., Di Fiore P. P. Eps8, a substrate for the epidermal growth factor receptor kinase, enhances EGF-dependent mitogenic signals. EMBO J. 1993 Oct;12(10):3799–3808. doi: 10.1002/j.1460-2075.1993.tb06058.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Freshney N. W., Rawlinson L., Guesdon F., Jones E., Cowley S., Hsuan J., Saklatvala J. Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell. 1994 Sep 23;78(6):1039–1049. doi: 10.1016/0092-8674(94)90278-x. [DOI] [PubMed] [Google Scholar]
  13. Gille H., Strahl T., Shaw P. E. Activation of ternary complex factor Elk-1 by stress-activated protein kinases. Curr Biol. 1995 Oct 1;5(10):1191–1200. doi: 10.1016/s0960-9822(95)00235-1. [DOI] [PubMed] [Google Scholar]
  14. Guan K. L., Dixon J. E. Eukaryotic proteins expressed in Escherichia coli: an improved thrombin cleavage and purification procedure of fusion proteins with glutathione S-transferase. Anal Biochem. 1991 Feb 1;192(2):262–267. doi: 10.1016/0003-2697(91)90534-z. [DOI] [PubMed] [Google Scholar]
  15. Gupta S., Barrett T., Whitmarsh A. J., Cavanagh J., Sluss H. K., Dérijard B., Davis R. J. Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 1996 Jun 3;15(11):2760–2770. [PMC free article] [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. Han J., Lee J. D., Jiang Y., Li Z., Feng L., Ulevitch R. J. Characterization of the structure and function of a novel MAP kinase kinase (MKK6). J Biol Chem. 1996 Feb 9;271(6):2886–2891. doi: 10.1074/jbc.271.6.2886. [DOI] [PubMed] [Google Scholar]
  18. Hanks S. K., Hunter T. Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 1995 May;9(8):576–596. [PubMed] [Google Scholar]
  19. 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]
  20. Janknecht R., Hunter T. Convergence of MAP kinase pathways on the ternary complex factor Sap-1a. EMBO J. 1997 Apr 1;16(7):1620–1627. doi: 10.1093/emboj/16.7.1620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jenkins J. R., Ayton P., Jones T., Davies S. L., Simmons D. L., Harris A. L., Sheer D., Hickson I. D. Isolation of cDNA clones encoding the beta isozyme of human DNA topoisomerase II and localisation of the gene to chromosome 3p24. Nucleic Acids Res. 1992 Nov 11;20(21):5587–5592. doi: 10.1093/nar/20.21.5587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kallunki T., Su B., Tsigelny I., Sluss H. K., Dérijard B., Moore G., Davis R., Karin M. JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation. Genes Dev. 1994 Dec 15;8(24):2996–3007. doi: 10.1101/gad.8.24.2996. [DOI] [PubMed] [Google Scholar]
  23. Kemp B. E., Pearson R. B. Protein kinase recognition sequence motifs. Trends Biochem Sci. 1990 Sep;15(9):342–346. doi: 10.1016/0968-0004(90)90073-k. [DOI] [PubMed] [Google Scholar]
  24. Kowenz-Leutz E., Twamley G., Ansieau S., Leutz A. Novel mechanism of C/EBP beta (NF-M) transcriptional control: activation through derepression. Genes Dev. 1994 Nov 15;8(22):2781–2791. doi: 10.1101/gad.8.22.2781. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Ludwig S., Engel K., Hoffmeyer A., Sithanandam G., Neufeld B., Palm D., Gaestel M., Rapp U. R. 3pK, a novel mitogen-activated protein (MAP) kinase-activated protein kinase, is targeted by three MAP kinase pathways. Mol Cell Biol. 1996 Dec;16(12):6687–6697. doi: 10.1128/mcb.16.12.6687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Moller D. E., Xia C. H., Tang W., Zhu A. X., Jakubowski M. Human rsk isoforms: cloning and characterization of tissue-specific expression. Am J Physiol. 1994 Feb;266(2 Pt 1):C351–C359. doi: 10.1152/ajpcell.1994.266.2.C351. [DOI] [PubMed] [Google Scholar]
  28. Rabindran S. K., Giorgi G., Clos J., Wu C. Molecular cloning and expression of a human heat shock factor, HSF1. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):6906–6910. doi: 10.1073/pnas.88.16.6906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Raingeaud J., Gupta S., Rogers J. S., Dickens M., Han J., Ulevitch R. J., Davis R. J. Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem. 1995 Mar 31;270(13):7420–7426. doi: 10.1074/jbc.270.13.7420. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Skolnik E. Y., Margolis B., Mohammadi M., Lowenstein E., Fischer R., Drepps A., Ullrich A., Schlessinger J. Cloning of PI3 kinase-associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases. Cell. 1991 Apr 5;65(1):83–90. doi: 10.1016/0092-8674(91)90410-z. [DOI] [PubMed] [Google Scholar]
  32. Sluss H. K., Barrett T., Dérijard B., Davis R. J. Signal transduction by tumor necrosis factor mediated by JNK protein kinases. Mol Cell Biol. 1994 Dec;14(12):8376–8384. doi: 10.1128/mcb.14.12.8376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Songyang Z., Blechner S., Hoagland N., Hoekstra M. F., Piwnica-Worms H., Cantley L. C. Use of an oriented peptide library to determine the optimal substrates of protein kinases. Curr Biol. 1994 Nov 1;4(11):973–982. doi: 10.1016/s0960-9822(00)00221-9. [DOI] [PubMed] [Google Scholar]
  34. Songyang Z., Lu K. P., Kwon Y. T., Tsai L. H., Filhol O., Cochet C., Brickey D. A., Soderling T. R., Bartleson C., Graves D. J. A structural basis for substrate specificities of protein Ser/Thr kinases: primary sequence preference of casein kinases I and II, NIMA, phosphorylase kinase, calmodulin-dependent kinase II, CDK5, and Erk1. Mol Cell Biol. 1996 Nov;16(11):6486–6493. doi: 10.1128/mcb.16.11.6486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Stein B., Brady H., Yang M. X., Young D. B., Barbosa M. S. Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade. J Biol Chem. 1996 May 10;271(19):11427–11433. doi: 10.1074/jbc.271.19.11427. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. Stokoe D., Caudwell B., Cohen P. T., Cohen P. The substrate specificity and structure of mitogen-activated protein (MAP) kinase-activated protein kinase-2. Biochem J. 1993 Dec 15;296(Pt 3):843–849. doi: 10.1042/bj2960843. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. 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]
  39. Umesono K., Murakami K. K., Thompson C. C., Evans R. M. Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors. Cell. 1991 Jun 28;65(7):1255–1266. doi: 10.1016/0092-8674(91)90020-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Valtorta F., Schiebler W., Jahn R., Ceccarelli B., Greengard P. A solid-phase assay for the phosphorylation of proteins blotted on nitrocellulose membrane filters. Anal Biochem. 1986 Oct;158(1):130–137. doi: 10.1016/0003-2697(86)90600-7. [DOI] [PubMed] [Google Scholar]
  41. Wadman I. A., Hsu H. L., Cobb M. H., Baer R. The MAP kinase phosphorylation site of TAL1 occurs within a transcriptional activation domain. Oncogene. 1994 Dec;9(12):3713–3716. [PubMed] [Google Scholar]
  42. Waskiewicz A. J., Flynn A., Proud C. G., Cooper J. A. Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J. 1997 Apr 15;16(8):1909–1920. doi: 10.1093/emboj/16.8.1909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wen Z., Zhong Z., Darnell J. E., Jr Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995 Jul 28;82(2):241–250. doi: 10.1016/0092-8674(95)90311-9. [DOI] [PubMed] [Google Scholar]
  44. Westendorf J. M., Rao P. N., Gerace L. Cloning of cDNAs for M-phase phosphoproteins recognized by the MPM2 monoclonal antibody and determination of the phosphorylated epitope. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):714–718. doi: 10.1073/pnas.91.2.714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Whitmarsh A. J., Shore P., Sharrocks A. D., Davis R. J. Integration of MAP kinase signal transduction pathways at the serum response element. Science. 1995 Jul 21;269(5222):403–407. doi: 10.1126/science.7618106. [DOI] [PubMed] [Google Scholar]
  46. 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]
  47. 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]
  48. Yang B. S., Hauser C. A., Henkel G., Colman M. S., Van Beveren C., Stacey K. J., Hume D. A., Maki R. A., Ostrowski M. C. Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2. Mol Cell Biol. 1996 Feb;16(2):538–547. doi: 10.1128/mcb.16.2.538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Yang X., Hubbard E. J., Carlson M. A protein kinase substrate identified by the two-hybrid system. Science. 1992 Jul 31;257(5070):680–682. doi: 10.1126/science.1496382. [DOI] [PubMed] [Google Scholar]
  50. Young R. A., Davis R. W. Efficient isolation of genes by using antibody probes. Proc Natl Acad Sci U S A. 1983 Mar;80(5):1194–1198. doi: 10.1073/pnas.80.5.1194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Zervos A. S., Faccio L., Gatto J. P., Kyriakis J. M., Brent R. Mxi2, a mitogen-activated protein kinase that recognizes and phosphorylates Max protein. Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10531–10534. doi: 10.1073/pnas.92.23.10531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Zhao Y., Bjørbaek C., Weremowicz S., Morton C. C., Moller D. E. RSK3 encodes a novel pp90rsk isoform with a unique N-terminal sequence: growth factor-stimulated kinase function and nuclear translocation. Mol Cell Biol. 1995 Aug;15(8):4353–4363. doi: 10.1128/mcb.15.8.4353. [DOI] [PMC free article] [PubMed] [Google Scholar]