Logo of embojLink to Publisher's site
EMBO J. Jun 15, 1998; 17(12): 3372–3384.
PMCID: PMC1170675

PRAK, a novel protein kinase regulated by the p38 MAP kinase.

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 (855K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Ben-Levy R, Leighton IA, Doza YN, Attwood P, Morrice N, Marshall CJ, Cohen P. Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2. EMBO J. 1995 Dec 1;14(23):5920–5930. [PMC free article] [PubMed]
  • 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. [PMC free article] [PubMed]
  • Bogoyevitch MA, Gillespie-Brown J, Ketterman AJ, Fuller SJ, Ben-Levy R, Ashworth A, Marshall CJ, Sugden PH. 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. [PubMed]
  • Boyle WJ, 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. [PubMed]
  • Cano E, Mahadevan LC. Parallel signal processing among mammalian MAPKs. Trends Biochem Sci. 1995 Mar;20(3):117–122. [PubMed]
  • Cano E, Doza YN, Ben-Levy R, Cohen P, Mahadevan LC. Identification of anisomycin-activated kinases p45 and p55 in murine cells as MAPKAP kinase-2. Oncogene. 1996 Feb 15;12(4):805–812. [PubMed]
  • Cowley S, Paterson H, Kemp P, Marshall CJ. 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. [PubMed]
  • Davis RJ. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem. 1993 Jul 15;268(20):14553–14556. [PubMed]
  • Dérijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M, Davis RJ. 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. [PubMed]
  • Dérijard B, Raingeaud J, Barrett T, Wu IH, Han J, Ulevitch RJ, Davis RJ. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995 Feb 3;267(5198):682–685. [PubMed]
  • 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. [PubMed]
  • Fanger GR, Gerwins P, Widmann C, Jarpe MB, Johnson GL. 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. [PubMed]
  • Foltz IN, Lee JC, Young PR, Schrader JW. 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. [PubMed]
  • 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. [PMC free article] [PubMed]
  • 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. [PMC free article] [PubMed]
  • Guan KL, Dixon JE. 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. [PubMed]
  • Guay J, Lambert H, Gingras-Breton G, Lavoie JN, 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. [PubMed]
  • 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]
  • Han J, Lee JD, Tobias PS, Ulevitch RJ. Endotoxin induces rapid protein tyrosine phosphorylation in 70Z/3 cells expressing CD14. J Biol Chem. 1993 Nov 25;268(33):25009–25014. [PubMed]
  • Han J, Lee JD, Bibbs L, Ulevitch RJ. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science. 1994 Aug 5;265(5173):808–811. [PubMed]
  • Han J, Lee JD, Jiang Y, Li Z, Feng L, Ulevitch RJ. Characterization of the structure and function of a novel MAP kinase kinase (MKK6). J Biol Chem. 1996 Feb 9;271(6):2886–2891. [PubMed]
  • Han J, Jiang Y, Li Z, Kravchenko VV, Ulevitch RJ. Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation. Nature. 1997 Mar 20;386(6622):296–299. [PubMed]
  • Holland PM, Suzanne M, Campbell JS, Noselli S, Cooper JA. MKK7 is a stress-activated mitogen-activated protein kinase kinase functionally related to hemipterous. J Biol Chem. 1997 Oct 3;272(40):24994–24998. [PubMed]
  • Huang CK, 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. [PubMed]
  • Huang S, Jiang Y, Li Z, Nishida E, Mathias P, Lin S, Ulevitch RJ, Nemerow GR, 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. [PubMed]
  • Huot J, Lambert H, Lavoie JN, 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. [PubMed]
  • 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. [PubMed]
  • Iordanov M, Bender K, Ade T, Schmid W, Sachsenmaier C, Engel K, Gaestel M, Rahmsdorf HJ, Herrlich P. CREB is activated by UVC through a p38/HOG-1-dependent protein kinase. EMBO J. 1997 Mar 3;16(5):1009–1022. [PMC free article] [PubMed]
  • 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. [PMC free article] [PubMed]
  • Jiang Y, Chen C, Li Z, Guo W, Gegner JA, 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. [PubMed]
  • Jiang Y, Gram H, Zhao M, New L, Gu J, Feng L, Di Padova F, Ulevitch RJ, 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. [PubMed]
  • Jones SW, Erikson E, Blenis J, Maller JL, Erikson RL. 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. [PMC free article] [PubMed]
  • 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. [PubMed]
  • 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. [PMC free article] [PubMed]
  • Lechner C, Zahalka MA, Giot JF, Møller NP, 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. [PMC free article] [PubMed]
  • Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Heys JR, Landvatter SW, et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994 Dec 22;372(6508):739–746. [PubMed]
  • Li Z, Jiang Y, Ulevitch RJ, 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. [PubMed]
  • 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. [PubMed]
  • Ludwig S, Engel K, Hoffmeyer A, Sithanandam G, Neufeld B, Palm D, Gaestel M, Rapp UR. 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. [PMC free article] [PubMed]
  • 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. [PubMed]
  • Marshall CJ. MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. Curr Opin Genet Dev. 1994 Feb;4(1):82–89. [PubMed]
  • McLaughlin MM, Kumar S, McDonnell PC, Van Horn S, Lee JC, Livi GP, Young PR. 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. [PubMed]
  • 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. [PubMed]
  • 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]
  • Perregaux DG, Dean D, Cronan M, Connelly P, Gabel CA. 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]
  • Price MA, Cruzalegui FH, 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]
  • Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ. 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. [PubMed]
  • Robinson MJ, Cobb MH. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol. 1997 Apr;9(2):180–186. [PubMed]
  • Rouse J, Cohen P, Trigon S, Morange M, Alonso-Llamazares A, Zamanillo D, Hunt T, Nebreda AR. 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. [PubMed]
  • Seger R, Krebs EG. The MAPK signaling cascade. FASEB J. 1995 Jun;9(9):726–735. [PubMed]
  • Stokoe D, Campbell DG, Nakielny S, Hidaka H, Leevers SJ, 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. [PMC free article] [PubMed]
  • Stokoe D, Engel K, Campbell DG, 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. [PubMed]
  • Su B, Karin M. Mitogen-activated protein kinase cascades and regulation of gene expression. Curr Opin Immunol. 1996 Jun;8(3):402–411. [PubMed]
  • Tan Y, Rouse J, Zhang A, Cariati S, Cohen P, Comb MJ. 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]
  • 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. [PubMed]
  • Tournier C, Whitmarsh AJ, Cavanagh J, Barrett T, Davis RJ. 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. [PMC free article] [PubMed]
  • Wang HC, Erikson RL. 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. [PMC free article] [PubMed]
  • Wang XS, Diener K, Manthey CL, Wang S, Rosenzweig B, Bray J, Delaney J, Cole CN, Chan-Hui PY, Mantlo N, et al. Molecular cloning and characterization of a novel p38 mitogen-activated protein kinase. J Biol Chem. 1997 Sep 19;272(38):23668–23674. [PubMed]
  • Wang XZ, 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. [PubMed]
  • Waskiewicz AJ, Cooper JA. 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. [PubMed]
  • Waskiewicz AJ, Flynn A, Proud CG, Cooper JA. Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J. 1997 Apr 15;16(8):1909–1920. [PMC free article] [PubMed]
  • Whitmarsh AJ, Shore P, Sharrocks AD, Davis RJ. Integration of MAP kinase signal transduction pathways at the serum response element. Science. 1995 Jul 21;269(5222):403–407. [PubMed]
  • Whitmarsh AJ, Yang SH, Su MS, Sharrocks AD, Davis RJ. 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. [PMC free article] [PubMed]
  • Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 1995 Nov 24;270(5240):1326–1331. [PubMed]
  • Yin T, Sandhu G, Wolfgang CD, Burrier A, Webb RL, Rigel DF, 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. [PubMed]
  • Zechner D, Thuerauf DJ, Hanford DS, McDonough PM, Glembotski CC. 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. [PMC free article] [PubMed]
  • Zhao Y, Bjorbaek C, Moller DE. Regulation and interaction of pp90(rsk) isoforms with mitogen-activated protein kinases. J Biol Chem. 1996 Nov 22;271(47):29773–29779. [PubMed]
  • Zu YL, Wu F, Gilchrist A, Ai Y, Labadia ME, Huang CK. The primary structure of a human MAP kinase activated protein kinase 2. Biochem Biophys Res Commun. 1994 Apr 29;200(2):1118–1124. [PubMed]

Articles from The EMBO Journal are provided here courtesy of The European Molecular Biology Organization

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • BioProject
    BioProject
    BioProject links
  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • Gene
    Gene
    Gene links
  • Gene (nucleotide)
    Gene (nucleotide)
    Records in Gene identified from shared sequence links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene
    HomoloGene links
  • MedGen
    MedGen
    Related information in MedGen
  • Nucleotide
    Nucleotide
    Published Nucleotide sequences
  • OMIM
    OMIM
    OMIM record citing PubMed
  • Pathways + GO
    Pathways + GO
    Pathways, annotations and biological systems (BioSystems) that cite the current article.
  • Protein
    Protein
    Published protein sequences
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...