PRAK, a novel protein kinase regulated by the p38 MAP kinase (original) (raw)

Abstract

We have identified and cloned a novel serine/ threonine kinase, p38-regulated/activated protein kinase (PRAK). PRAK is a 471 amino acid protein with 20-30% sequence identity to the known MAP kinase-regulated protein kinases RSK1/2/3, MNK1/2 and MAPKAP-K2/3. PRAK was found to be expressed in all human tissues and cell lines examined. In HeLa cells, PRAK was activated in response to cellular stress and proinflammatory cytokines. PRAK activity was regulated by p38alpha and p38beta both in vitro and in vivo and Thr182 was shown to be the regulatory phosphorylation site. Activated PRAK in turn phosphorylated small heat shock protein 27 (HSP27) at the physiologically relevant sites. An in-gel kinase assay demonstrated that PRAK is a major stress-activated kinase that can phosphorylate small heat shock protein, suggesting a potential role for PRAK in mediating stress-induced HSP27 phosphorylation in vivo.

Full Text

The Full Text of this article is available as a PDF (855.1 KB).

Selected References

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

  1. 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]
  2. 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]
  3. Bogoyevitch M. A., Gillespie-Brown J., Ketterman A. J., Fuller S. J., Ben-Levy R., Ashworth A., Marshall C. J., Sugden P. H. Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion. Circ Res. 1996 Aug;79(2):162–173. doi: 10.1161/01.res.79.2.162. [DOI] [PubMed] [Google Scholar]
  4. Boyle W. J., van der Geer P., Hunter T. Phosphopeptide mapping and phosphoamino acid analysis by two-dimensional separation on thin-layer cellulose plates. Methods Enzymol. 1991;201:110–149. doi: 10.1016/0076-6879(91)01013-r. [DOI] [PubMed] [Google Scholar]
  5. Cano E., Doza Y. N., Ben-Levy R., Cohen P., Mahadevan L. C. Identification of anisomycin-activated kinases p45 and p55 in murine cells as MAPKAP kinase-2. Oncogene. 1996 Feb 15;12(4):805–812. [PubMed] [Google Scholar]
  6. 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]
  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. Davis R. J. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem. 1993 Jul 15;268(20):14553–14556. [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. Edery I., Altmann M., Sonenberg N. High-level synthesis in Escherichia coli of functional cap-binding eukaryotic initiation factor eIF-4E and affinity purification using a simplified cap-analog resin. Gene. 1988 Dec 30;74(2):517–525. doi: 10.1016/0378-1119(88)90184-9. [DOI] [PubMed] [Google Scholar]
  12. Fanger G. R., Gerwins P., Widmann C., Jarpe M. B., Johnson G. L. MEKKs, GCKs, MLKs, PAKs, TAKs, and tpls: upstream regulators of the c-Jun amino-terminal kinases? Curr Opin Genet Dev. 1997 Feb;7(1):67–74. doi: 10.1016/s0959-437x(97)80111-6. [DOI] [PubMed] [Google Scholar]
  13. Foltz I. N., Lee J. C., Young P. R., Schrader J. W. Hemopoietic growth factors with the exception of interleukin-4 activate the p38 mitogen-activated protein kinase pathway. J Biol Chem. 1997 Feb 7;272(6):3296–3301. doi: 10.1074/jbc.272.6.3296. [DOI] [PubMed] [Google Scholar]
  14. Fukunaga R., Hunter T. MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. EMBO J. 1997 Apr 15;16(8):1921–1933. doi: 10.1093/emboj/16.8.1921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Goedert M., Cuenda A., Craxton M., Jakes R., Cohen P. Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases. EMBO J. 1997 Jun 16;16(12):3563–3571. doi: 10.1093/emboj/16.12.3563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. Guay J., Lambert H., Gingras-Breton G., Lavoie J. N., Huot J., Landry J. Regulation of actin filament dynamics by p38 map kinase-mediated phosphorylation of heat shock protein 27. J Cell Sci. 1997 Feb;110(Pt 3):357–368. doi: 10.1242/jcs.110.3.357. [DOI] [PubMed] [Google Scholar]
  18. Han J., Huez G., Beutler B. Interactive effects of the tumor necrosis factor promoter and 3'-untranslated regions. J Immunol. 1991 Mar 15;146(6):1843–1848. [PubMed] [Google Scholar]
  19. Han J., Jiang Y., Li Z., Kravchenko V. V., Ulevitch R. J. Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation. Nature. 1997 Mar 20;386(6622):296–299. doi: 10.1038/386296a0. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. 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]
  22. Han J., Lee J. D., Tobias P. S., Ulevitch R. J. Endotoxin induces rapid protein tyrosine phosphorylation in 70Z/3 cells expressing CD14. J Biol Chem. 1993 Nov 25;268(33):25009–25014. [PubMed] [Google Scholar]
  23. Holland P. M., Suzanne M., Campbell J. S., Noselli S., Cooper J. A. MKK7 is a stress-activated mitogen-activated protein kinase kinase functionally related to hemipterous. J Biol Chem. 1997 Oct 3;272(40):24994–24998. doi: 10.1074/jbc.272.40.24994. [DOI] [PubMed] [Google Scholar]
  24. Huang C. K., Zhan L., Ai Y., Jongstra J. LSP1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils. J Biol Chem. 1997 Jan 3;272(1):17–19. doi: 10.1074/jbc.272.1.17. [DOI] [PubMed] [Google Scholar]
  25. Huang S., Jiang Y., Li Z., Nishida E., Mathias P., Lin S., Ulevitch R. J., Nemerow G. R., Han J. Apoptosis signaling pathway in T cells is composed of ICE/Ced-3 family proteases and MAP kinase kinase 6b. Immunity. 1997 Jun;6(6):739–749. doi: 10.1016/s1074-7613(00)80449-5. [DOI] [PubMed] [Google Scholar]
  26. Huot J., Houle F., Marceau F., Landry J. Oxidative stress-induced actin reorganization mediated by the p38 mitogen-activated protein kinase/heat shock protein 27 pathway in vascular endothelial cells. Circ Res. 1997 Mar;80(3):383–392. doi: 10.1161/01.res.80.3.383. [DOI] [PubMed] [Google Scholar]
  27. Huot J., Lambert H., Lavoie J. N., Guimond A., Houle F., Landry J. Characterization of 45-kDa/54-kDa HSP27 kinase, a stress-sensitive kinase which may activate the phosphorylation-dependent protective function of mammalian 27-kDa heat-shock protein HSP27. Eur J Biochem. 1995 Jan 15;227(1-2):416–427. doi: 10.1111/j.1432-1033.1995.tb20404.x. [DOI] [PubMed] [Google Scholar]
  28. Iordanov M., Bender K., Ade T., Schmid W., Sachsenmaier C., Engel K., Gaestel M., Rahmsdorf H. J., Herrlich P. CREB is activated by UVC through a p38/HOG-1-dependent protein kinase. EMBO J. 1997 Mar 3;16(5):1009–1022. doi: 10.1093/emboj/16.5.1009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. 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]
  30. Jiang Y., Chen C., Li Z., Guo W., Gegner J. A., Lin S., Han J. Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). J Biol Chem. 1996 Jul 26;271(30):17920–17926. doi: 10.1074/jbc.271.30.17920. [DOI] [PubMed] [Google Scholar]
  31. Jiang Y., Gram H., Zhao M., New L., Gu J., Feng L., Di Padova F., Ulevitch R. J., Han J. Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38delta. J Biol Chem. 1997 Nov 28;272(48):30122–30128. doi: 10.1074/jbc.272.48.30122. [DOI] [PubMed] [Google Scholar]
  32. Jones S. W., Erikson E., Blenis J., Maller J. L., Erikson R. L. A Xenopus ribosomal protein S6 kinase has two apparent kinase domains that are each similar to distinct protein kinases. Proc Natl Acad Sci U S A. 1988 May;85(10):3377–3381. doi: 10.1073/pnas.85.10.3377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Kawasaki H., Morooka T., Shimohama S., Kimura J., Hirano T., Gotoh Y., Nishida E. Activation and involvement of p38 mitogen-activated protein kinase in glutamate-induced apoptosis in rat cerebellar granule cells. J Biol Chem. 1997 Jul 25;272(30):18518–18521. doi: 10.1074/jbc.272.30.18518. [DOI] [PubMed] [Google Scholar]
  34. Knauf U., Jakob U., Engel K., Buchner J., Gaestel M. Stress- and mitogen-induced phosphorylation of the small heat shock protein Hsp25 by MAPKAP kinase 2 is not essential for chaperone properties and cellular thermoresistance. EMBO J. 1994 Jan 1;13(1):54–60. doi: 10.1002/j.1460-2075.1994.tb06234.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Lechner C., Zahalka M. A., Giot J. F., Møller N. P., Ullrich A. ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4355–4359. doi: 10.1073/pnas.93.9.4355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. 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]
  37. Li Z., Jiang Y., Ulevitch R. J., Han J. The primary structure of p38 gamma: a new member of p38 group of MAP kinases. Biochem Biophys Res Commun. 1996 Nov 12;228(2):334–340. doi: 10.1006/bbrc.1996.1662. [DOI] [PubMed] [Google Scholar]
  38. Lu X., Nemoto S., Lin A. Identification of c-Jun NH2-terminal protein kinase (JNK)-activating kinase 2 as an activator of JNK but not p38. J Biol Chem. 1997 Oct 3;272(40):24751–24754. doi: 10.1074/jbc.272.40.24751. [DOI] [PubMed] [Google Scholar]
  39. 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]
  40. Marais R., Wynne J., Treisman R. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell. 1993 Apr 23;73(2):381–393. doi: 10.1016/0092-8674(93)90237-k. [DOI] [PubMed] [Google Scholar]
  41. 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]
  42. McLaughlin M. M., Kumar S., McDonnell P. C., Van Horn S., Lee J. C., Livi G. P., Young P. R. Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase. J Biol Chem. 1996 Apr 5;271(14):8488–8492. doi: 10.1074/jbc.271.14.8488. [DOI] [PubMed] [Google Scholar]
  43. Mertens S., Craxton M., Goedert M. SAP kinase-3, a new member of the family of mammalian stress-activated protein kinases. FEBS Lett. 1996 Apr 1;383(3):273–276. doi: 10.1016/0014-5793(96)00255-4. [DOI] [PubMed] [Google Scholar]
  44. Nagata Y., Moriguchi T., Nishida E., Todokoro K. Activation of p38 MAP kinase pathway by erythropoietin and interleukin-3. Blood. 1997 Aug 1;90(3):929–934. [PubMed] [Google Scholar]
  45. Perregaux D. G., Dean D., Cronan M., Connelly P., Gabel C. A. Inhibition of interleukin-1 beta production by SKF86002: evidence of two sites of in vitro activity and of a time and system dependence. Mol Pharmacol. 1995 Sep;48(3):433–442. [PubMed] [Google Scholar]
  46. Price M. A., Cruzalegui F. H., Treisman R. The p38 and ERK MAP kinase pathways cooperate to activate Ternary Complex Factors and c-fos transcription in response to UV light. EMBO J. 1996 Dec 2;15(23):6552–6563. [PMC free article] [PubMed] [Google Scholar]
  47. 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]
  48. Robinson M. J., Cobb M. H. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol. 1997 Apr;9(2):180–186. doi: 10.1016/s0955-0674(97)80061-0. [DOI] [PubMed] [Google Scholar]
  49. 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]
  50. Seger R., Krebs E. G. The MAPK signaling cascade. FASEB J. 1995 Jun;9(9):726–735. [PubMed] [Google Scholar]
  51. 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]
  52. Stokoe D., Engel K., Campbell D. G., Cohen P., Gaestel M. Identification of MAPKAP kinase 2 as a major enzyme responsible for the phosphorylation of the small mammalian heat shock proteins. FEBS Lett. 1992 Nov 30;313(3):307–313. doi: 10.1016/0014-5793(92)81216-9. [DOI] [PubMed] [Google Scholar]
  53. Su B., Karin M. Mitogen-activated protein kinase cascades and regulation of gene expression. Curr Opin Immunol. 1996 Jun;8(3):402–411. doi: 10.1016/s0952-7915(96)80131-2. [DOI] [PubMed] [Google Scholar]
  54. Tan Y., Rouse J., Zhang A., Cariati S., Cohen P., Comb M. J. FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J. 1996 Sep 2;15(17):4629–4642. [PMC free article] [PubMed] [Google Scholar]
  55. Thomas G., Haavik J., Cohen P. Participation of a stress-activated protein kinase cascade in the activation of tyrosine hydroxylase in chromaffin cells. Eur J Biochem. 1997 Aug 1;247(3):1180–1189. doi: 10.1111/j.1432-1033.1997.01180.x. [DOI] [PubMed] [Google Scholar]
  56. Tournier C., Whitmarsh A. J., Cavanagh J., Barrett T., Davis R. J. Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase. Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7337–7342. doi: 10.1073/pnas.94.14.7337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Wang H. C., Erikson R. L. Activation of protein serine/threonine kinases p42, p63, and p87 in Rous sarcoma virus-transformed cells: signal transduction/transformation-dependent MBP kinases. Mol Biol Cell. 1992 Dec;3(12):1329–1337. doi: 10.1091/mbc.3.12.1329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Wang X. S., Diener K., Manthey C. L., Wang S., Rosenzweig B., Bray J., Delaney J., Cole C. N., Chan-Hui P. Y., Mantlo N. Molecular cloning and characterization of a novel p38 mitogen-activated protein kinase. J Biol Chem. 1997 Sep 19;272(38):23668–23674. doi: 10.1074/jbc.272.38.23668. [DOI] [PubMed] [Google Scholar]
  59. Wang X. Z., Ron D. Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase. Science. 1996 May 31;272(5266):1347–1349. doi: 10.1126/science.272.5266.1347. [DOI] [PubMed] [Google Scholar]
  60. Waskiewicz A. J., Cooper J. A. Mitogen and stress response pathways: MAP kinase cascades and phosphatase regulation in mammals and yeast. Curr Opin Cell Biol. 1995 Dec;7(6):798–805. doi: 10.1016/0955-0674(95)80063-8. [DOI] [PubMed] [Google Scholar]
  61. 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]
  62. 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]
  63. Whitmarsh A. J., Yang S. H., Su M. S., Sharrocks A. D., Davis R. J. Role of p38 and JNK mitogen-activated protein kinases in the activation of ternary complex factors. Mol Cell Biol. 1997 May;17(5):2360–2371. doi: 10.1128/mcb.17.5.2360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Xia Z., Dickens M., Raingeaud J., Davis R. J., Greenberg M. E. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 1995 Nov 24;270(5240):1326–1331. doi: 10.1126/science.270.5240.1326. [DOI] [PubMed] [Google Scholar]
  65. Yin T., Sandhu G., Wolfgang C. D., Burrier A., Webb R. L., Rigel D. F., Hai T., Whelan J. Tissue-specific pattern of stress kinase activation in ischemic/reperfused heart and kidney. J Biol Chem. 1997 Aug 8;272(32):19943–19950. doi: 10.1074/jbc.272.32.19943. [DOI] [PubMed] [Google Scholar]
  66. Zechner D., Thuerauf D. J., Hanford D. S., McDonough P. M., Glembotski C. C. A role for the p38 mitogen-activated protein kinase pathway in myocardial cell growth, sarcomeric organization, and cardiac-specific gene expression. J Cell Biol. 1997 Oct 6;139(1):115–127. doi: 10.1083/jcb.139.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Zhao Y., Bjorbaek C., Moller D. E. Regulation and interaction of pp90(rsk) isoforms with mitogen-activated protein kinases. J Biol Chem. 1996 Nov 22;271(47):29773–29779. doi: 10.1074/jbc.271.47.29773. [DOI] [PubMed] [Google Scholar]
  68. Zu Y. L., Wu F., Gilchrist A., Ai Y., Labadia M. E., Huang C. K. The primary structure of a human MAP kinase activated protein kinase 2. Biochem Biophys Res Commun. 1994 Apr 29;200(2):1118–1124. doi: 10.1006/bbrc.1994.1566. [DOI] [PubMed] [Google Scholar]