Skip to main content

Advertisement

SpringerLink
Log in

Heat shock protein 27 phosphorylation: kinases, phosphatases, functions and pathology

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The small heat shock protein Hsp27 or its murine homologue Hsp25 acts as an ATP-independent chaperone in protein folding, but is also implicated in architecture of the cytoskeleton, cell migration, metabolism, cell survival, growth/differentiation, mRNA stabilization, and tumor progression. A variety of stimuli induce phosphorylation of serine residues 15, 78, and 82 in Hsp27 and serines 15 and 86 in Hsp25. This post-translational modification affects some of the cellular functions of Hsp25/27. As a consequence of the functional importance of Hsp25/27 phosphorylation, aberrant Hsp27 phosphorylation has been linked to several clinical conditions. This review focuses on the different Hsp25/27 kinases and phosphatases that regulate the phosphorylation pattern of Hsp25/27, and discusses the recent findings of the biological implications of these phosphorylation events in physiological and pathological processes. Novel therapeutic strategies aimed at restoring anomalous Hsp27 phosphorylation in human diseases will be presented.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Gusev NB, Bogatcheva NV, Marston SB (2002) Structure and properties of small heat shock proteins (sHsp) and their interaction with cytoskeleton proteins. Biochemistry 67:511–519

    PubMed  CAS  Google Scholar 

  2. Kappe G, Franck E, Verschuure P, Boelens WC, Leunissen JA, de Jong WW (2003) The human genome encodes 10 α-crystallin-related small heat shock proteins: HspB1–10. Cell Stress Chaperones 8:53–61

    PubMed  CAS  Google Scholar 

  3. Lelj-Garolla B, Mauk AG (2005) Self-association of a small heat shock protein. J Mol Biol 345:631–642

    PubMed  CAS  Google Scholar 

  4. Ferns G, Shams S, Shafi S (2006) Heat shock protein 27: its potential role in vascular disease. Int J Exp Path 87:253–274

    CAS  Google Scholar 

  5. Lavoie JN, Gingras-Breton G, Tanguay RM, Landry J (1993) Induction of chinese hamster Hsp27 gene expression in mouse cells confers resistance to heat shock. J Biol Chem 268:3420–3429

    PubMed  CAS  Google Scholar 

  6. Arata S, Hamaguchi S, Nose K (1997) Inhibition of colony formation of NIH 3T3 cells by the expression of the small molecular weight heat shock protein HSP27: involvement of its phosphorylation and aggregation at the C-terminal region. J Cell Physiol 170:19–26

    PubMed  CAS  Google Scholar 

  7. Blackburn RV, Galoforo SS, Berns CM, Armour EP, McEachern D, Corry PM, Lee YJ (1997) Comparison of tumor growth between Hsp25- and Hsp27-transfected murine L929 cells in nude mice. Int J Cancer 72:871–877

    PubMed  CAS  Google Scholar 

  8. Hedges JC, Dechert MA, Yamboliev IA, Martin JL, Hickey E, Weber LA, Gerthoffer WT (1999) A role for p38(MAPK)/HSP27 pathway in smooth muscle cell migration. J Biol Chem 274:24211–24219

    PubMed  CAS  Google Scholar 

  9. Cooper LF, Uoshima K (1994) Differential estrogenic regulation of small Mr heat shock protein expression in osteoblasts. J Biol Chem 269:7869–7873

    PubMed  CAS  Google Scholar 

  10. Spector NL, Mehlen P, Ryan C, Hardly L, Samson W, Levine H, Nadler LM, Fabre N, Arrigo AP (1994) Regulation of the 28 kDa heat shock protein by retinoic acid during differentiation of human leukemic HL-60 cells. FEBS Lett 337:184–188

    PubMed  CAS  Google Scholar 

  11. Murashov AK, Ul Haq I, Hill C, Park E, Smith M, Wang X, Wang X, Goldberg DJ, Wolgemuth DJ (2001) Crosstalk between p38, Hsp25 and Akt in spinal motor neurons after sciatic nerve injury. Mol Brain Res 93:199–208

    PubMed  CAS  Google Scholar 

  12. Okada T, Otani H, Wu Y, Kyoi S, Enoki C, Fujiwara H, Sumida T, Hattori R, Imamura H (2005) Role of F-actin organization in p38 MAP kinase-mediated apoptosis and necrosis in neonatal rat cardiomyocytes subjected to stimulated ischemia and reoxygenation. Am J Physiol Heart Circ Physiol 289:H2310–H2318

    PubMed  CAS  Google Scholar 

  13. Welsh MJ, Gaestel M (1997) Small heat-shock protein family: function in health and disease. Ann N Y Acad Sci 851:28–35

    Google Scholar 

  14. Bukach OV, Glukhova AE, Seit-Nebi AS, Gusev NB (2009) Heterooligomeric complexes formed by human small heat shock proteins HspB1 (Hsp27) and HspB6 (Hsp20). Biochim Biophys Acta 1794:486–495

    PubMed  CAS  Google Scholar 

  15. Lambert H, Charette SJ, Bernier AF, Guimond A, Landry J (1999) Hsp27 multimerization mediated by phosphorylation-sensitive intermolecular interactions at the amino terminus. J Biol Chem 274:9378–9385

    PubMed  CAS  Google Scholar 

  16. Sun X, Welsh MJ, Benndorf R (2006) Conformational changes resulting from pseudophosphorylation of mammalian small heat shock proteins–a two-hybrid study. Cell Stress Chaperones 11:61–70

    PubMed  CAS  Google Scholar 

  17. Jakob U, Gaestel M, Engel K, Buchner J (1993) Small heat shock proteins are molecular chaperones. J Biol Chem 268:1517–1520

    PubMed  CAS  Google Scholar 

  18. Knauf U, Jakob U, Engel K, Buchner J, Gaestel M (1994) 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 13:54–60

    PubMed  CAS  Google Scholar 

  19. Ehrnsperger M, Gräber S, Gaestel M, Buchner J (1997) Binding of non-native protein to Hsp25 during heat shock creates a reservoir of folding intermediates for reactivation. EMBO J 16:221–229

    PubMed  CAS  Google Scholar 

  20. Vos MJ, Hageman J, Carra S, Kampinga H (2008) Structural and functional diversities between members of the human HSPB, HSPH, HSPA, and DNAJ chaperone families. Biochemistry 47:7001–7011

    PubMed  CAS  Google Scholar 

  21. Rogalla T, Ehrnsperger M, Preville X, Kotlyarov A, Lutsch G, Ducasse C, Paul C, Wieske M, Arrigo AP, Buchner J, Gaestel M (1999) Regulation of Hsp27 oligomerization, chaperone function, and protective activity against oxidative stress/tumor necrosis factor α by phosphorylation. J Biol Chem 274:18947–18956

    PubMed  CAS  Google Scholar 

  22. Kato K, Ito H, Iwamoto I, Iida K, Inaguma Y (2001) Protein kinase inhibitors can suppress stress-induced dissociation of Hsp27. Cell Stress Chaperones 6:16–20

    PubMed  CAS  Google Scholar 

  23. Spector NL, Ryan C, Samson W, Levine H, Nadler LM, Arrigo AP (1993) Heat shock protein is a unique marker of growth arrest during macrophage differentiation of HL-60 cells. J Cell Physiol 156:619–625

    PubMed  CAS  Google Scholar 

  24. Kindas-Mugge I, Trautinger F (1994) Increased expression of the Mr 27, 000 heat shock protein (hsp27) in in vitro differentiated normal human keratiinocytes. Cell Growth Differ 5:777–781

    PubMed  CAS  Google Scholar 

  25. Charrette SJ, Lavoie JN, Lambert H, Landry J (2000) Inhibition of Daxx-mediated apoptosis by heat shock protein 27. Mol Cell Biol 20:7602–7612

    Google Scholar 

  26. Lasa M, Mahtani KR, Finch A, Brewer G, Saklatavla J, Clark AR (2000) Regulation of cyclooxygenase 2 mRNA stability by the mitogen-activated protein kinase p38 signaling cascade. Mol Cell Biol 20:4265–4272

    PubMed  CAS  Google Scholar 

  27. Calderwood SK, Khaleque MA, Sawyer DB, Ciocca DR (2006) Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem Sci 31:164–172

    PubMed  CAS  Google Scholar 

  28. Patil SB, Pawar MD, Bitar KN (2004) Phosphorylated HSP27 is essential for acetylcholine-induced association of RhoA with PKCα. Am J Physiol Gastrointest Liver Physiol 286:G635–G644

    PubMed  CAS  Google Scholar 

  29. Gerthoffer WT (2005) Signal-transduction pathways that regulate visceral smooth muscle function. III. Coupling of muscarinic receptors to signaling kinases and effector proteins in gastrointestinal smooth muscles. Am J Physiol Gastrointest Liver Physiol 288:G849–G853

    PubMed  CAS  Google Scholar 

  30. Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G (2006) Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell Cycle 5:2592–2601

    PubMed  CAS  Google Scholar 

  31. Alford KA, Glennie S, Rawlinson L, Saklatvala J, Dean JL (2007) Heat shock protein 27 functions in inflammatory gene expression and transforming growth factor-beta-activated kinase-1 (TAK1)-mediated signaling. J Biol Chem 282:6232–6241

    PubMed  CAS  Google Scholar 

  32. Arrigo AP (2007) The cellular “networking” of mammalian Hsp27 and its functions in the control of protein folding, redox state and apoptosis. Adv Exp Med Biol 594:14–26

    PubMed  Google Scholar 

  33. Wu R, Kausar H, Johnson P, Montoya-Durango DE, Merchant M, Rane MJ (2007) Hsp27 regulates Akt activation and polymporphonuclear leukocyte apoptosis by scaffolding MK2 to Akt signal complex. J Biol Chem 282:21598–21608

    PubMed  CAS  Google Scholar 

  34. Sinsimer KS, Gratacós FM, Knapinska AM, Lu J, Krause CD, Wierzbowski AV, Mahler LR, Scrudato S, Rivera YM, Gupta S, Turrin DK, De La Cruz MP, Pestka S, Brewer G (2008) Chaperone Hsp27, a novel subunit of AUF1 protein complexes, functions in AU-rich element-mediated mRNA decay. Mol Cell Biol 28:5223–5237

    PubMed  CAS  Google Scholar 

  35. Stetler RA, Ca G, Gao Y, Zhang F, Wang S, Wenig Z, Vosler P, Zhang L, Signore A, Graham SH, Chen J (2008) Hsp27 protects against ischemic brain injury via attenuation of a novel stress-response cascade upstream of mitochondrial cell death signaling. J Neurosci 28:13038–13055

    PubMed  CAS  Google Scholar 

  36. Doshi BM, Hightower LE, Lee J (2009) The role of Hsp27 and actin in the regulation of movement in human cancer cells responding to heat shock. Cell Stress Chaperones. Feb 18 [Epub ahead of print]. doi:10.1007/s12192-008-1

  37. Landry J, Lambert H, Zhou M, Lavoie JN, Hickey E, Weber LA, Anderson CW (1992) Human Hsp27 is phosphorylated at serine 78 and 82 by heat shock and mitogen-activated protein kinases that recognize the same amino acid motif as S6 kinase II. J Biol Chem 267:794–803

    PubMed  CAS  Google Scholar 

  38. Zhou M, Lambert H, Landry J (1993) Transient activation of a distinct serine protein kinase is responsible for 27-kDa heat shock protein phosphorylation in mirogen-stimulated and heat-shocked cells. J Biol Chem 268:35–43

    PubMed  CAS  Google Scholar 

  39. Préville X, Schultz H, Knauf U, Gaestel M, Arrigo AP (1998) Analysis of the role of Hsp25 phosphorylation reveals the importance of the oligomerization state of this small heat shock protein in its protective function against TNFalpha- and hydrogen peroxide-induced cell death. J Cell Biochem 69:436–453

    PubMed  Google Scholar 

  40. Lavoie JN, Lambert H, Hickey E, Weber LA, Landry J (1995) Modulation of cellular thermoresistance and actin filament stability accompanies phosphorylation-induced changes in the oligomeric structure of heat shock protein 27. Mol Cell Biol 15:505–516

    PubMed  CAS  Google Scholar 

  41. Geum D, Son GH, Kim K (2002) Phosphorylation-dependent cellular localization and thermoprotective role of heat shock protein 25 in hippocampal progenitor cells. J Biol Chem 277:19913–19921

    PubMed  CAS  Google Scholar 

  42. Huot J, Houle F, Spitz DR, Landry J (1996) Hsp27 phosphorylation-mediated resistance against actin fragmentation and cell death induced by oxidative stress. Cancer Res 56:273–279

    PubMed  CAS  Google Scholar 

  43. Lee YJ, Lee DH, Cho CK, Bae S, Jhon GJ, Lee SJ, Soh JW, Lee YS (2005) Hsp25 inhibits protein kinase Cδ-mediated cell death through direct interaction. J Biol Chem 280:18108–18119

    PubMed  CAS  Google Scholar 

  44. Benn SC, Perrelet D, Kato AC, Scholz J, Decosterd I, Mannion RJ, Bakowska JC, Woolf CJ (2002) Hsp27 upregulation and phosphorylation is required for injury sensory and motor neuron survival. Neuron 36:45–56

    PubMed  CAS  Google Scholar 

  45. Wyttenbach A, Sauvageot O, Carmichael J, Diaz-Latoud C, Arrigo AP, Rubinsztein DC (2002) Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin. Hum Mol Genet 11:1137–1151

    PubMed  CAS  Google Scholar 

  46. de Graauw M, Tijdens I, Cramer R, Corless S, Timms JF, van de Water B (2005) Heat shock protein 27 is the major differentially phosphorylated protein involved in renal epithelial cellular stress response and controls focal adhesion organization and apoptosis. J Biol Chem 280:29885–29898

    PubMed  Google Scholar 

  47. Winger QA, Guttormsen J, Gavin H, Bhushan F (2007) Heat shock protein 1 and the mitogen-activated protein kinase 14 pathway are important for mouse trophoblast stem cell differentiation. Biol Reprod 76:884–891

    PubMed  CAS  Google Scholar 

  48. Evgrafov OV, Mersiyanova I, Irobi J, Van Den Bosch L, Dierick I, Leung CL, Schagina O, Verpoorten N, Van Impe K, Fedotov V, Dadali E, Auer-Grumbach M, Windpassinger C, Wagner K, Mitrovic Z, Hilton-Jones D, Talbot K, Martin JJ, Vasserman N, Tverskaya S, Polyakov A, Liem RK, Gettemans J, Robberecht W, De Jonghe P, Timmerman V (2004) Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet 36:602–606

    PubMed  CAS  Google Scholar 

  49. Chen S, Brown IR (2007) Neuronal expression of constitutive heat shock proteins: implications for neurodegenerative diseases. Cell Stress Chaperones 12:51–58

    PubMed  CAS  Google Scholar 

  50. Calderwood SK, Ciocca DR (2008) Heat shock proteins: stress proteins with Janus-like properties in cancer. Int J Hyperthermia 24:31–39

    PubMed  CAS  Google Scholar 

  51. Houlden H, Laura M, Wavrant-De Vrièze F, Blake J, Wood N, Reilly MM (2008) Mutations in the HSP27 (HSPB1) gene cause dominant, recessive, and sporadic distal HMN/CMT type 2. Neurology 71:1660–1668

    PubMed  CAS  Google Scholar 

  52. Robaye B, Hepburn A, Lecocq R, Fiers W, Boeynaems JM, Dumont JE (1989) Tumor necrosis factor-alpha induces the phosphorylation of 28kDa stress proteins in endothelial cells: possible role in protection against cytotoxicity? Biochem Biophys Res Commun 163:301–308

    PubMed  CAS  Google Scholar 

  53. Arrigo AP, Michel MR (1991) Decreased heat- and tumor necrosis factor-mediated Hsp28 phosphorylation in thermotolerant HeLa cells. FEBS Lett 282:152–156

    PubMed  CAS  Google Scholar 

  54. Cuenda A, Rouse J, Doza YN, Meier R, Cohen P, Gallagher TF, Young PR, Lee JC (1995) SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett 364:229–233

    PubMed  CAS  Google Scholar 

  55. Clifton AD, Young PR, Cohen P (1996) A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAP kinase-3 and their activation by cytokines and cellular stress. FEBS Lett 392:209–214

    PubMed  CAS  Google Scholar 

  56. Tilly BC, Gaestel M, Engel K, Edixhoven MJ, de Jonge HR (1996) Hypo-osmotic cell swelling activates the p38 MAP kinase signalling cascade. FEBS Lett 395:133–136

    PubMed  CAS  Google Scholar 

  57. Buitrago CG, Ronda AC, de Boland AR, Boland R (2006) MAP kinase p38 and JNK are activated by the steroid hormone 1α, 25(OH)2-vitamin D3 in the C2C12 muscle cell line. J Cell Biochem 97:698–708

    PubMed  CAS  Google Scholar 

  58. Suga, H, Nakajima K, Shu E, Kanno Y, Hirade K, Ishisaki A, Matsuno H, Tanabe K, Takai S, Akamatsu S, Kato K, Oiso Y, Kozawa, O (2005) Possible involvement of phosphatidylinositol 3-kinase/Akt signal pathway in vasopressin-induced Hsp27 phosphorylation in aortic smooth muscle A10 cells. Arch Biochem Biophys 438:137–145

    PubMed  Google Scholar 

  59. Park JK, Ronkina N, Höft A, Prohl C, Menne J, Gaestel M, Haller H, Meier M (2008) Deletion of MK2 signalling in vivo inhibits small Hsp phosphorylation but not diabetic nephropathy. Nephrol Dial Transplant 23:1844–1853

    PubMed  CAS  Google Scholar 

  60. Thomas T, Hitti E, Kotlyarov A, Potschka H, Gaestel M (2008) MAP-kinase-activated protein kinase 2 expression and activity is induced after neuronal depolarization. Eur J NeuroSci 28:642–654

    PubMed  Google Scholar 

  61. Hickey E, Brandon SE, Potter R, Stein G (1986) Sequence and organization of genes encoding the human 27 kDa heat shock protein. Nucleic Acids Res 14:4127–4145

    PubMed  CAS  Google Scholar 

  62. Gaestel M, Schröder W, Benndorf R, Lippmann C, Buchner K, Hucho F, Erdmann VA, Bielka H (1991) Identification of the phosphorylation sites of the murine small heat shock protein Hsp25. J Biol Chem 266:14721–14724

    PubMed  CAS  Google Scholar 

  63. Gardner KH, Montminy M (2005) Can you hear me now? Regulating transcriptional activators by phosphorylation. Sci STKE 301, pe44

  64. Benndorf R, Hayes K, Stahl J, Bielka H (1992) Cell-free phosphorylation of the murine small heat-shock protein hsp25 by an endogenous kinase from Erhlich ascites tumor cells. Biochim Biophys Acta 1136:203–207

    PubMed  CAS  Google Scholar 

  65. Stokoe D, Engel K, Campbell DG, Cohen P, Gaestel M (1992) Identification of MAPKAP kinase 2 as a major enzyme responsible for the phosphorylation of the small mammalian heat shock proteins. FEBS Lett 313:307–313

    PubMed  CAS  Google Scholar 

  66. Rouse J, Cohen P, Trigon S, Morange M, Alonso-Llamazares A, Zamanillo D, Hunt T, Nebreda AR (1994) A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell 78:1027–1037

    PubMed  CAS  Google Scholar 

  67. Ahlers A, Belka C, Gaestel M, Lamping N, Sott C, Herrmann F, Brach MA (1994) Interleukin-1-induced intracellular signaling pathways converge in the activation of mitogen-activated protein kinase and mitogen-activated protein kinase-activated protein kinase 2 and the subsequent phosphorylation of the 27-kilodalton heat shock protein in monocytic cells. Mol Pharmacol 46:1077–1083

    PubMed  CAS  Google Scholar 

  68. Larsen JK, Yamboliev IA, Weber LA, Gerthoffer WT (1997) Phosphorylation of the 27-kDa heat shock protein via p38 MAP kinase and MAPKAP kinase in smooth muscle. Am J Physiol 273:L930–L940

    PubMed  CAS  Google Scholar 

  69. Rousseau S, Houle F, Landry J, Huot J (1997) p38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. Oncogene 15:2169–2177

    PubMed  CAS  Google Scholar 

  70. Azuma N, Akasaka N, Kito H, Ikeda M, Gahtan V, Sasajima T, Sumpio BE (2001) Role of p38 MAP kinase in endothelial cell alignment induced by fluid shear stress. Am J Physiol Heart Circ Physiol 280:H189–H197

    PubMed  CAS  Google Scholar 

  71. Huot J, Lambert H, Lavoie JN, Guimond A, Houle F, Landry J (1995) 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 227:416–427

    PubMed  CAS  Google Scholar 

  72. Pietersma A, Tilly BC, Gaeste M, de Jong N, Lee JC, Koster JF, Sluiter W (1997) p38 mitogen activated protein kinase regulates endothelial VCAM-1 expression at the post-transcriptional level. Biochem Biophys Res Comm 230:44–48

    PubMed  CAS  Google Scholar 

  73. Schäfer C, Ross SE, Bragado MJ, Groblewski GE, Ernst SA, Williams JA (1998) A role for the p38 mitogen-activated protein kinase/Hsp27 pathway in cholecystokinin-induced changes in the actin cytoskeleton in rat pancreatic acini. J Biol Chem 273:24173–24180

    PubMed  Google Scholar 

  74. Chevalier D, Allen BG (2000) Two distinct forms of MAPKAP kinase-2 in adult cardiac ventricular myocytes. Biochemistry 39:6145–6156

    PubMed  CAS  Google Scholar 

  75. Kayyali US, Pennella CM, Trujillo C, Villa O, Gaestel M, Hassoun PM (2002) Cytoskeletal changes in hypoxia pulmonary endothelial cells are dependent on MAPK-activated protein kinase MK2. J Biol Chem 277:42596–42602

    PubMed  CAS  Google Scholar 

  76. Shi Y, Kotlyarov A, Laasz K, Gruber AD, Butt E, Marcus K, Meyer HE, Friedrich A, Volk HD, Gaestel M (2003) Elimination of protein kinase MK5/PRAK activity by targeted homologous recombination. Mol Cell Biol 23:7732–7741

    PubMed  CAS  Google Scholar 

  77. Rousseau S, Dolado I, Beardmore V, Shpiro N, Marquez R, Nebreda AR, Arthur JS, Case LM, Tessier-Lavigne M, Gaestel M, Cuenda A, Cohen P (2006) CXCL12 and C5a trigger cell migration via a PAK1/2–p38α MAPK-MAPKAP-K2-Hsp27 pathway. Cell Signal 18:1897–1905

    PubMed  CAS  Google Scholar 

  78. Huot J, Houle F, Marceau F, Landry J (1997) Oxidative stress-induced actin reorganization mediated by the p38 mitogen-activated protein kinase/heat shock protein 27 pathway in vascular endothelial cells. Circ Res 80:383–392

    PubMed  CAS  Google Scholar 

  79. Ronkina N, Kotlyarov A, Gaestel M (2008) MK2 and MK3–a pair of isoenzymes? Front Biosci 13:5511–5521

    PubMed  CAS  Google Scholar 

  80. McLaughlin MM, Kumar S, McDonnell PC, Van Horn S, Lee JC, Livi GP, Young PR (1996) Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase. J Biol Chem 271:8488–8492

    PubMed  CAS  Google Scholar 

  81. Zakowski V, Keramas G, Kilian K, Rapp UR, Ludwig S (2004) Mitogen-activated 3p kinase is active in the nucleus. Exp Cell Res 299:101–109

    PubMed  CAS  Google Scholar 

  82. New L, Jiang Y, Zhao M, Liu K, Zhu W, Flood LJ, Kato Y, Parry GCN, Han J (1998) PRAK, a novel protein kinase regulated by the p38 MAP kinase. EMBO J 17:3372–3384

    PubMed  CAS  Google Scholar 

  83. Ni H, Wang XS, Diener K, Yao Z (1998) MAPKAPK5, a novel mitogen-activated protein kinase (MAPK)-activated protein kinase, is a substrate of the extracellular-regulated kinase (ERK) and p38 kinase. Biochem Biophys Res Commun 243:492–496

    PubMed  CAS  Google Scholar 

  84. Gaestel M (2006) MAPKAP kinases- MKs–two’s company, three’s a crowd. Nat Rev Mol Cell Biol 7:120–130

    PubMed  CAS  Google Scholar 

  85. Polanowska-Gabrowska R, Gear AR (2000) Heat-shock proteins and platelet function. Platelets 11:6–22

    Google Scholar 

  86. Gerits N, Mikalsen T, Kostenko S, Shiryaev A, Johannessen M, Moens U (2007) Modulation of F-actin rearrangement by the cyclic AMP/cAMP-dependent protein kinase (PKA) pathway is mediated by MAPK-activated protein kinase 5 and requires PKA-induced nuclear export of MK5. J Biol Chem 282:37232–37243

    PubMed  CAS  Google Scholar 

  87. Tak H, Jang E, Kim SB, Park J, Suk J, Yoon YS, Ahn JK, Lee J-H, Joe CO (2007) 14-3-3epsilon inhibits MK5-mediated cell migration by disrupting F-actin polymerization. Cell Signal 19:2379–2387

    PubMed  CAS  Google Scholar 

  88. Kostenko S, Johannessen M, Moens U (2009) PKA-induced F-actin rearrangement requires phosphorylation of Hsp27 by the MAPKAP kinase MK5. Cell Signal 21:712–718

    PubMed  CAS  Google Scholar 

  89. Sithanandam G, Latif F, Duh FM, Bernal R, Smola U, Li H, Kuzmin I, Wixler V, Geil L, Shrestha S (1996) 3pK, a new mitogen-activated protein kinase-activated protein kinase located in the small cell lung cancer tumor suppressor gene region. Mol Cell Biol 16:868–876

    PubMed  CAS  Google Scholar 

  90. Cairns J, Qin S, Philp R, Tan YH, Guy GR (1994) Dephosphorylaton of the small heat shock protein Hsp27 in vivo by protein phosphatase 2A. J Biol Chem 269:9176–9183

    PubMed  CAS  Google Scholar 

  91. Butt E, Immler D, Meyer HE, Kotlyarov A, Laass K, Gaestel M (2001) Heat shock protein 27 is a substrate of cGMP-dependent protein kinase in intact human platelets. J Biol Chem 276:7108–7113

    PubMed  CAS  Google Scholar 

  92. Huang SY, Tsai ML, Chen GY, Wu CJ, Chen SH (2007) A systematic MS-based approach for identifying in vitro substrates of PKA and PKG in rat uteri. J Proteome Res 6:2674–2684

    PubMed  CAS  Google Scholar 

  93. Saklatvala J, Guedson F (1991) Interleukin 1 signal transduction. Agents Actions Suppl 35:35–40

    PubMed  CAS  Google Scholar 

  94. Nakajima K, Hirade K, Ishisaki A, Matsuno H, Suga H, Kanno Y, Shu E, Kitajima Y, Katagiri Y, Kozawa O (2005) Akt regulates thrombin-induced Hsp27 phosphorylation in aortic smooth muscle cells: function at a point downstream from p38 MAP kinase. Life Sci 77:96–107

    PubMed  CAS  Google Scholar 

  95. Lamb NJC, Fernandez A, Feramisco JR, Welch WJ (1989) Modulation of vimentin containing intermediate filament distribution and phosphorylation in living fibroblasts by the cAMP-dependent protein kinase. J Cell Biol 108:2409–2422

    PubMed  CAS  Google Scholar 

  96. Gerits N, Shiryaev A, Kostenko S, Klenow H, Shiryaeva O, Johannessen M, Moens U (2009) Transcriptional regulation and cell-specific expression of the mitogen-activated protein kinase-activated protein kinase MK5. Cell Mol Biol Lett. May 30. [Epub ahead of print]. doi:10.2478/s11658-009-0020-6

  97. Michel JJ, Scott JD (2002) AKAP mediated signal transduction. Annu Rev Pharmacol Toxicol 42:235–257

    PubMed  CAS  Google Scholar 

  98. Konishi H, Matsuzaki H, Tanaka M, Takemura Y, Kuroda S, Ono Y, Kikkawa U (1997) Activation of protein kinase B (Akt/Rac-protein kinase) by cellular stress and its association with heat shock protein Hsp27. FEBS Lett 410:493–498

    PubMed  CAS  Google Scholar 

  99. Rane MJ, Coxon PY, Powell DW, Webster R, Klein JB, Ping P, Pierce W, McLeish KR (2001) p38 Kinase-dependent MAPKAPK-2 activation functions as 3-phosphoinositide-dependent kinase-2 for Akt in human neutrophils. J Biol Chem 276:3517–3523

    PubMed  CAS  Google Scholar 

  100. Rane MJ, Pan Y, Singh S, Powell DW, Wu R, Cummins T, Chen Q, McLeish KR, Klein JB (2003) Heat shock protein 27 controls apoptosis by regulating Akt activation. J Biol Chem 278:27826–27835

    Google Scholar 

  101. Fukagawa Y, Nishikawa J, Kuramitsu Y, Iwakiri D, Takada K, Imai S, Satake M, Okamoto T, Fujimoto M, Okita K, Nakamura K, Sakaida I (2008) Epstein-Barr virus upregulates phosphorylated heat shock protein 27 kDa in carcinoma cells using the phosphoinositide 3-kinase/Akt pathway. Electrophoresis 29:3192–3200

    PubMed  CAS  Google Scholar 

  102. O’Shaughnessy RFL, Welti JC, Cooke JC, Avillion AA, Monks B, Birnbaum MJ, Byrne C (2007) AKT-dependent HspB1 (Hsp27) activity in epidermal differentiation. J Biol Chem 282:17297–17305

    PubMed  Google Scholar 

  103. Mearow KM, Dodge ME, Rahimtula M, Yegappan C (2002) Stress-mediated signaling in PC12 cells—the role of the small heat shock protein, Hsp27, and Akt in protecting cells from heat stress and nerve growth factor withdrawal. J Neurochem 83:452–462

    PubMed  CAS  Google Scholar 

  104. Alessi DR, Andjelkovich M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15:6541–6551

    PubMed  CAS  Google Scholar 

  105. Feuerstein N, Cooper HL (1983) Rapid protein phosphorylation induced by phorbol ester in HL-60 cells. Unique alkali-stable phosphorylation of a 17, 000-dalton protein detected by two-dimensional gel electrophoresis. J Biol Chem 258:10786–10793

    PubMed  CAS  Google Scholar 

  106. Santell L, Bartfeld NS, Levin EG (1992) Identification of a protein transiently phosphorylated by activators of endothelial function as the heat-shock protein HSP27. Biochem J 284:705–710

    PubMed  CAS  Google Scholar 

  107. Evans IM, Britton G, Zachary IC (2008) Vascular endothelial growth factor induces heat shock protein (HSP) 27 serine 82 phosphorylation and endothelial tubulogenesis via protein kinase D and independent of p38 kinase. Cell Signal 20:1375–1384

    PubMed  CAS  Google Scholar 

  108. Maizels ET, Peters CA, Kline M, Cutler RE Jr, Shanmugam M, Hunzicker-Dunn M (1998) Heat-schock protein-25/27 phosphorylation by the δ isoform of protein kinase C. Biochem J 332:703–712

    PubMed  CAS  Google Scholar 

  109. Schultz H, Engel K, Gaestel M (1997) PMA-induced activation of the p42/44ERK- and p38RK-MAP kinase cascades in HL-60 cells is PKC dependent but not essential for differentiation to the macrophage-like phenotype. J Cell Physiol 173:310–318

    PubMed  CAS  Google Scholar 

  110. Takai S, Matsushima-Nishiwaki R, Tokuda H, Yasuda E, Toyoda H, Kaneoka Y, Yamaguchi A, Kumada T, Kozawa O (2007) Protein kinase C delta regulates the phosphorylation of heat shock protein 27 in human hepatocellular carcinoma. Life Sci 81:585–591

    PubMed  CAS  Google Scholar 

  111. Van Lint J, Ryckx A, Vantus T, Vandenheede JR (2002) Getting to know protein kinase D. Int J Biochem Cell Biol 34:577–581

    PubMed  Google Scholar 

  112. Döppler H, Storz P, Li J, Comb MJ, Toker A (2005) A phosphorylatin state-specific antibody recognizes Hsp27, a novel substrate of protein kinase D. J Biol Chem 280:15013–15019

    PubMed  Google Scholar 

  113. Liu P, Scharenber AM, Cantrell DA, Matthews SA (2007) Protein kinase D enzymes are dispensable for proliferation, survival and antigen receptor-regulated NFκB activity in vertebrate B-cells. FEBS Lett 581:1377–1382

    PubMed  CAS  Google Scholar 

  114. McMullen ME, Bryant PW, Glembotski CC, Vincent PA, Pumiglia KM (2005) Activation of p38 has opposing effects on the proliferation and migration of endothelial cells. J Biol Chem 280:20995–21003

    PubMed  CAS  Google Scholar 

  115. Kobayashi M, Nishita M, Mishima T, Ohashi K, Mizuno K (2007) MAPKAPK-2-mediated LIM-kinase activation is critical for VEGF-induced actin remodeling and cell migration. EMBO J 25:713–726

    Google Scholar 

  116. Yuan J, Rozengurt E (2008) PDK, PDK2, and p38 MAPK mediate Hsp27 serine-82 phosphorylation induced by neurotensin in pancreatic cancer PANC-1 cells. J Cell Biochem 103:648–662

    PubMed  CAS  Google Scholar 

  117. Storz P, Stoker A (2003) Protein kinase D mediates a stress-induced NF-kappaB activation and survival pathway. EMBO J 22:109–120

    PubMed  CAS  Google Scholar 

  118. Arrigo AP (2001) Hsp27: novel regulator of intracellular redox state. IUMMB 52:303–307

    CAS  Google Scholar 

  119. Walter U, Gambaryan S (2009) cGMP and cGMP-dependent protein kinase in platelets and blood cells. Handb Exp Pharmacol 191:533–548

    PubMed  CAS  Google Scholar 

  120. Huang S-Y, Tsai M-L, Wu C-J, Hsu J-L, Ho S-H, Chen S-H (2006) Quantitation of protein phosphorylation in pregnant rat uteri using stable isotope dimethyl labeling coupled with IMAC. Proteomics 6:1722–1734

    PubMed  CAS  Google Scholar 

  121. Kim SO, Xu Y, Katz S, Pelech S (2000) Cyclic GMP-dependent and -independent regulation of MAP kinases by sodium nitroprusside in isolated cardiomyocytes. Biochim Biophys Acta 1496:277–284

    PubMed  CAS  Google Scholar 

  122. Cai H, Liu D, Garcia JG (2008) CaM Kinase II-dependent pathophysiological signalling in endothelial cells. Cardiovac Res 77:30–34

    CAS  Google Scholar 

  123. Levin EG, Santell L (1991) Phosphorylation of an Mr = 29, 000 protein by IL-1 is susceptible to partial down-regulation after endothelial cell activation. J Immunol 146:3772–3778

    PubMed  CAS  Google Scholar 

  124. Loktionova SA, Kabakov AE (1998) Protein phosphatase inhibitors and heat preconditioning prevent Hsp27 dephosphorylation, F-actin disruption and deterioration of morphology in ATP-depleted endothelial cells. FEBS Lett 433:294–300

    PubMed  CAS  Google Scholar 

  125. Tar K, Csortos C, Czikora I, Olah G, Ma SF, Wadgaonkar R, Gergely P, Garcia JG, Verin AD (2006) Role of protein phosphatase 2A in the regulation of endothelial cell cytoskeleton structure. J Cell Biochem 98:931–953

    PubMed  CAS  Google Scholar 

  126. Berrou E, Bryckaert M (2009) Recruitment of protein phosphatase 2A to dorsal ruffles by platelet-derived growth factor in smooth muscle cells: dephosphorylation of Hsp27. Exp Cell Res 315:836–848

    PubMed  CAS  Google Scholar 

  127. Gaestel M, Benndorf R, Hayess K, Priemer E, Engel K (1992) Dephosphorylation of the small heat shock protein hsp25 by calcium/calmodulin-dependent (type 2B) protein phosphatase. J Biol Chem 267:21607–21611

    PubMed  CAS  Google Scholar 

  128. Stokoe D, Campbell DG, Nakielny S, Hikada H, Leevers SJ, Marshall C, Cohen P (1992) MAPKAP kinase-2; a novel protein kinase activated by mitogen-activated protein kinase. EMBO J 11:3985–3994

    PubMed  CAS  Google Scholar 

  129. Miron T, Vancompernollle K, Vandekerckhove J, Wilchek M, Geiger B (1991) A 25-kD inhibitor of actin polymerization is a low molecular mass heat shock protein. J Cell Biol 114:255–261

    PubMed  CAS  Google Scholar 

  130. Lavoie JN, Hickey E, Weber LA, Landry J (1993) Modulation of actin microfilament dynamics and fluid phase pinocytosis by phosphorylation of heat shock protein 27. J Biol Chem 268:24210–24214

    PubMed  CAS  Google Scholar 

  131. Benndorf R, Hayess K, Ryazantsev S, Wieske M, Behlke J, Lutsch G (1994) Phosphorylation and supramolecular organization of murine small heat shock protein Hsp25 abolish its actin polymerization-inhibiting activity. J Biol Chem 269:20780–20784

    PubMed  CAS  Google Scholar 

  132. Huot J, Houle F, Rousseau S, Deschesnes RG, Shah GM, Landry J (1998) SAPK2/p38-dependent F-actin reorganization regulates early membrane blebbing during stress-induced apoptosis. J Cell Biol 143:1361–1373

    PubMed  CAS  Google Scholar 

  133. Piotrowicz RS, Hickey E, Levin EG (1998) Heat shock protein 27 kDa expression and phosphorylation regulates endothelial cell migration. FASEB J 12:1481–1490

    PubMed  CAS  Google Scholar 

  134. Dalle-Donne I, Rossi R, Milzani A, Di Simplicio P, Colombo R (2001) The actin cytoskeleton response to oxidants: from small heat shock protein phosphorylation to changes in the redox state of actin itself. Free Radic Biol Med 31:1624–1632

    PubMed  CAS  Google Scholar 

  135. Chen HF, Xie LD, Xu CS (2009) Role of heat shock protein 27 phosphorylation in migration of vascular smooth muscle cells. Mol Cell Biochem 327:1–6

    PubMed  CAS  Google Scholar 

  136. Hong Z, Zhang QY, Liu J, Wang ZQ, Zhang Y, Xiao Q, Lu J, Zhou HY, Chen S (2009) Phosphoproteome study reveals Hsp27 as a novel signaling molecule involved in GDNF-induced neurite outgrowth. J Proteome Res 8:2768–2787

    PubMed  CAS  Google Scholar 

  137. Gaestel M, Gross B, Benndorf R, Strauus M, Schunk WH, Kraft R, Otto A, Böhm H, Stahl J, Drabsch H, Bielka H (1989) Molecular cloning, sequencing and expression in Escherichia coli of the 25-kDa growth-related protein of Ehrlich ascites tumor and its homology to mammalian stress proteins. Eur J Biochem 179:209–213

    PubMed  CAS  Google Scholar 

  138. Oesterreich S, Benndorf R, Bielka H (1990) The expression of the growth-related 25kDa protein (p25) of Ehrlich ascites tumor cells is increased by hyperthermic treatment (heat shock). Biomed Biochim Acta 49:219–226

    PubMed  CAS  Google Scholar 

  139. Shibanuma M, Kuroki T, Nose K (1992) Cell-cycle dependent phosphorylation of HSP28 by TGF beta 1 and H2O2 in normal mouse osteoblastic cells (MC3T3–E1), but not in their ras-transformants. Biochem Bipophys Res Commun 187:1418–1425

    CAS  Google Scholar 

  140. Sullivan CM, Smith DM, Matsui NM, Andrews LE, Clauser KR, Chapeaurouge A, Burlingame AL, Epstein LB (1997) Identification of constitutive and gamma-interferon- and interleukin 4-regulated proteins in the human renal carcinoma cell line ACHN. Cancer Res 57:1137–1143

    PubMed  CAS  Google Scholar 

  141. Matsushima-Nishiwaki R, Takai S, Adachi S, Minamitani C, Yasuda E, Noda T, Kato K, Toyoda H, Kaneoka Y, Yamaguchi A, Kumada T, Kozawa O (2008) Phosphorylated heat shock protein 27 represses growth of hepatocellular carcinoma via inhibition of extracellular signal-regulated kinase. J Biol Chem 283:18852–18860

    PubMed  CAS  Google Scholar 

  142. Venkatakrishnan CD, Dunsmore K, Wong H, Roy S, Sen CK, Wani A, Zweier JL, Ilangovan G (2008) Hsp27 regulates p53 transcriptional activity in doxorubicin treated fibroblasts and cardiac H9c2 cells: upregulation and G2/M phase cell cycle arrest. Am J Physiol Heart Circ Physiol 294:H1736–H1744

    PubMed  CAS  Google Scholar 

  143. O’Callaghan-Sunol C, Gabai VL, Sherman MY (2007) Hsp27 modulates p53 signaling and suppresses cellular senescence. Cancer Res 67:11779–11788

    PubMed  Google Scholar 

  144. Suomalainen M, Nakano MY, Boucke K, Keller S, Greber UF (2001) Adenovirus-activated PKA and p38/MAPK pathways boost microtubule-mediated nuclear targeting of virus. EMBO J 20:1310–1319

    PubMed  CAS  Google Scholar 

  145. Schultz H, Rogalla T, Engel K, Lee JC, Gaestel M (1997) The protein kinase inhibitor SB203580 uncouples PMA-induced differentiation of HL-60 cells from phosphorylation of Hsp27. Cell Stress Chaperones 2:41–49

    PubMed  CAS  Google Scholar 

  146. Kato H, Takai S, Matsushima-Nishiwaki R, Adachi S, Minamitani C, Otsuka T, Tokuda H, Akamatsu S, Doi T, Ogura S, Kozawa O (2008) Hsp27 phosphorylation is correlated with ADP-induced platelet granule secretion. Arch Biochem Biophys 475:80–86

    PubMed  CAS  Google Scholar 

  147. Arrigo AP, Simon S, Gibert B, Kretiz-Remy C, Nivon M, Czekalla A, Guillet D, Moulin M, Diaz-Latoud C, Vicart P (2007) Hsp27 (HspB1) and αB-crystallin (HspB5) as therapeutic targets. FEBS Lett 581:3665–3674

    PubMed  CAS  Google Scholar 

  148. Madsen PS, Hokland P, Clausen N, Ellegaard J, Hokland M (1995) Differential expression of the heat shock protein 27 isoforms in pediatric normal, nonleukemic and common acute lymphoblastic leukemia B-cells precursors. Blood 85:510–521

    PubMed  CAS  Google Scholar 

  149. Tremolada L, Magni F, Valsecchi C, Sarto C, Mocarelli P, Perego R, Cordani N, Favini P, Galli Kienle M, Sanchez JC, Hochstrasser DF, Corthals GL (2005) Characterization of heat shock protein 27 phosphorylation sites in renal cell carcinoma. Proteomics 5:788–795

    PubMed  CAS  Google Scholar 

  150. Yasuda E, Kumada T, Takai S, Ishisaki A, Noda T, Matsushima-Nishiwaki R, Yoshimi N, Kato K, Toyoda H, Kaneoka Y, Yamaguchi A, Kozawa O (2005) Attenuated phosphorylation of heat shock protein 27 correlates with tumor progression in patients with hepatocellular carcinoma. Biochem Bipophys Res Commun 337:337–342

    CAS  Google Scholar 

  151. Song H, Ethier SP, Dziubinski ML, Lin J (2004) Stat3 modulates heat shock 27 kDa protein expression in breast epithelial cells. Biochem Bipophys Res Commun 314:143–150

    CAS  Google Scholar 

  152. Clevenger CV (2004) Roles and regulation of stat family transcription factors in human breast cancer. Am J Pathol 165:1449–1460

    PubMed  CAS  Google Scholar 

  153. So A, Hadaschik B, Sowery R, Gleave M (2007) The role of stress proteins in prostate cancer. Curr Genomics 8:252–261

    PubMed  CAS  Google Scholar 

  154. Berkowitz P, Hu P, Liu Z, Diaz LA, Enghild JJ, Chua MP, Rubenstein DS (2005) Desmosome signaling. Inhibition of p38MAPK prevents pemphigus vulgaris IgG-induced cytoskeleton reorganization. J Biol Chem 280:23778–23784

    PubMed  CAS  Google Scholar 

  155. Berkowitz P, Diaz LA, Hall RP, Rubenstein DS (2008) Induction of p38MAPK and Hsp27 phosphorylation in pemphigus patient skin. J Invest Dermatol 128:738–740

    PubMed  CAS  Google Scholar 

  156. Berkowitz P, Chua M, Liu Z, Diaz LA, Rubenstein DS (2008) Autoantibodies in the autoimmune disease pemphigus foliaceus induce blistering via p38 mitogen-activated protein kinase-dependent signalling in the skin. Am J Pathol 173:1628–1636

    PubMed  CAS  Google Scholar 

  157. Lee HE, Berkowitz P, Jolly PS, Diaz LA, Chun MP, Rubenstein DS (2009) Biphasic activation of p38MAPK suggests that apoptosis is a downstream event in pemphigus acantholysis. J Biol Chem 284:12524–12532

    PubMed  CAS  Google Scholar 

  158. Atkins D, Lichtenfels R, Seliger B (2005) Heat shock proteins in renal cell carcinomas. Contrib Nephrol 148:35–56

    PubMed  CAS  Google Scholar 

  159. Smoyer WE, Gupta A, Mundel P, Ballew JD, Welsh MJ (1996) Altered expression of glomerular heat shock protein 27 in experimental nephrotic syndrome. J Clin Invest 97:2697–2704

    PubMed  CAS  Google Scholar 

  160. Dai T, Natarajan R, Nast CC, LaPage J, Chuang P, Sim J, Tong L, Chamberlin M, Wang S, Adler SG (2006) Glucose and diabetes: effects on podocyte and glomerular p38MAPK, heat shock protein 25, and actin cytoskeleton. Kidney Int 69:806–814

    PubMed  CAS  Google Scholar 

  161. Barutta F, Pinach S, Giunti S, Vittone F, Forbes JM, Chiarle R, Arnstein M, Perin PC, Camussi G, Copper ME, Gruden G (2008) Heat shock protein expression in diabetic nephropathy. Am J Physiol Renal Physiol 295:F1817–F1824

    PubMed  CAS  Google Scholar 

  162. Ludwig S, Engel K, Hoffmeyer A, Sithanandam G, Neufeld B, Palm D, Gaestel M, Rapp UR (1996) 3pK, a novel mitogen-activated protein (MAP) kinase-activated protein kinase, is targeted by three MAP kinase pathways. Mol Cell Biol 16:6687–6697

    PubMed  CAS  Google Scholar 

  163. Kim MS, Kewalramani G, Puthanveetil P, Lee V, Kumar U, An D, Abramani A, Rodrigues B (2008) Acute diabetes moderates trafficking of cardiac lipoprotein lipase through p38 mitogen-activated protein kinase-dependent actin cytoskeleton organization. Diabetes 57:64–76

    PubMed  CAS  Google Scholar 

  164. Kim MS, Wang F, Puthanveetil P, Kewalramani G, Hosseini-Beheshti E, Ng N, Wang Y, Kumar U, Innis S, Proud CG, Abramani A, Rodrigues B (2008) Protein kinase D is a key regulator of cardiomyocyte lipoprotein lipase secretion after diabetes. Circ Res 103:252–260

    PubMed  CAS  Google Scholar 

  165. Vidyasagar A, Reese S, Acun Z, Hullett D, Djamali A (2008) Hsp27 is involved in the pathogenesis of kidney tubulointerstitial fibrosis. Am J Physiol Renal Physiol 295:F707–F716

    PubMed  CAS  Google Scholar 

  166. Singh D, McCann KL, Imani F (2007) MAPK and heat shock protein 27 activation are associated with respiratory syncytial virus induction of human bronchial epithelial monolayer disruption. Am J Physiol Lung Cell Mol Physiol 293:L436–L445

    PubMed  CAS  Google Scholar 

  167. Collins PL, Crowe JE Jr (2007) Respiratory syncytial virus and metapneumovirus. In: Knipe DM, Howley PM (eds) Fields virology. Lippincott Williams & Wilkins, Philadelphia, pp 1601–1646

    Google Scholar 

  168. Gooch C, Shy M (2008) Hereditary motor neuropathy and heat shock proteins: a shocking transformation. Neurology 71:1656–1657

    PubMed  Google Scholar 

  169. Dierick I, Baets J, Irobi J, Jacobs A, De Vriendt E, Deconinck T, Merlini L, Van den Bergh P, Rasic VM, Robberecht W, Fischer D, Morales RJ, Mitrovic Z, Seeman P, Mazanec R, Kochanski A, Jordanova A, Auer-Grumbach M, Helderman-van den Enden AT, Wokke JH, Nelis E, De Jonghe P, Timmerman V (2008) Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study. Brain 131:1217–1227

    PubMed  Google Scholar 

  170. Kamada M, So A, Muramaki M, Rocchi P, Beraldi E, Gleave M (2007) Hsp27 knockdown using nucleotide-based therapies inhibit tumor growth and enhance chemotherapy in human bladder cancer cells. Mol Cancer Ther 6:299–308

    PubMed  CAS  Google Scholar 

  171. Zu YL, Ai YX, Huang CK (1995) Characterization of an auto-inhibitory domain in human mitogen-activated protein kinase-activated protein kinase-2. J Biol Chem 270:202–206

    PubMed  CAS  Google Scholar 

  172. Hayess K, Benndorf R (1997) Effect of protein kinase inhibitors on activity of mammalian small heat-shock protein (Hsp25) kinase. Biochem Pharmacol 53:1239–1247

    PubMed  CAS  Google Scholar 

  173. Folmer F, Blasius R, Morceau F, Tabudravu J, Dicato M, Jaspars M, Diederich M (2006) Inhibition of TNFα-induced activation of nuclear factor κB by kava (Piper methysticum) derivatives. Biochem Pharmacol 71:1206–1218

    PubMed  CAS  Google Scholar 

  174. Mikalsen T, Gerits N, Moens U (2006) Inhibitors of signal transduction protein kinases as targets for cancer therapy. Biotechnol Ann Rev 12:153–223

    CAS  Google Scholar 

  175. Anderson DR, Meyers MJ, Vernier WF, Mahoney MW, Kurumbail RG, Caspers N, Poda GI, Schindler JF, Reitz DB, Mourey RJ (2007) Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). J Med Chem 50:2647–2654

    PubMed  CAS  Google Scholar 

  176. Schlapbach A, Feifel R, Hawtin S, Heng R, Koch G, Moebitz H, Revesz L, Scheufler C, Velcicky J, Waelchli R, Huppertz C (2008) Pyrrolo-pyrimidones: a novel class of MK2 inhibitors with potent cellular activity. Bioorg Med Chem Lett 18:142–146

    Google Scholar 

  177. Lopes LB, Flynn C, Komalavilas P, Panitch A, Brophy CM, Seal BL (2009) Inhibitor of Hsp27 phosphorylation by a cell-permeant MAPKAP kinase 2 inhibitor. Biochem Biophys Res Commun 382:535–539

    PubMed  CAS  Google Scholar 

  178. Damarla M, Hasan E, Boueiz A, Le A, Pae HH, Montouchet C, Kolb T, Simms T, Myers A, Kayyali US, Gaestel M, Peng X, Reddy SP, Damico R, Hassoun PM (2009) Mitogen activated protein kinase activated protein kinase 2 regulates actin polymerization and vascular leak in ventilator associated lung injury. PLoS One 4:e4600

    PubMed  Google Scholar 

  179. Shin KD, Lee M-Y, Shin D-S, Lee S, Son K-H, Koh S, Paik Y-Y, Kwon B-M, Han DC (2008) Blocking tumor cell migration and invasion with biphenyl isoxazole derivative KRIBB3, a synthetic molecule that inhibits Hsp27 phosphorylation. J Biol Chem 280:41439–41448

    Google Scholar 

  180. Wang RE, Kao JL, Hilliard CA, Pandita RK, Roti Roti JL, Hunt CR, Taylor JS (2009) Inhibition of heat shock induction of heat shock protein 70 and enhancement of heat shock protein 27 phosphorylation by quercetin derivatives. J Med Chem 52:1912–1921

    PubMed  CAS  Google Scholar 

  181. Hollander JM, Martin JL, Belke DD, Scott BT, Swanson E, Krishnamoorthy V, Dillmann WH (2004) Overexpression of wild-type heat shock protein 27 and a nonphosphorylatable heat shock 27 mutant protects against ischemia/reperfusion injury in a transgenic mouse model. Circulation 110:3544–3552

    PubMed  CAS  Google Scholar 

  182. Kubisch C, Dimagno MJ, Tietz AB, Welsh MJ, Ernst SA, Brandt-Nedelev B, Diebold J, Wagner AC, Göke B, Williams JA, Schäfer C (2004) Overexpression of heat shock protein Hsp27 protects against cerulean-induced pancreatitis. Gastroenterology 127:275–286

    PubMed  CAS  Google Scholar 

  183. Malki S, Nef S, Notarnicola C, Thevenet L, Gasca S, Méjean C, Berta P, Poulat F, Boizet-Bonhoure B (2005) Prostaglandin D2 induces nuclear import of the sex-determining factor SOX9 via its cAMP-PKA phosphorylation. EMBO J 24:1798–1809

    PubMed  CAS  Google Scholar 

  184. Seterens OM, Johansen B, Hegge B, Johannessen M, Keyse SM, Moens U (2002) Both binding and activation of p38 mitogen-activated protein kinase (MAPK) play essential roles in regulation of the nucleocytoplasmic distribution of MAPK-activated protein kinase 5 by cell stress. Mol Cell Biol 22:6931–6945

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Microbiology and Virology, Faculty of Medicine, University of Tromsø, 9037, Tromsø, Norway

    Sergiy Kostenko & Ugo Moens

Authors
  1. Sergiy Kostenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ugo Moens
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ugo Moens.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kostenko, S., Moens, U. Heat shock protein 27 phosphorylation: kinases, phosphatases, functions and pathology. Cell. Mol. Life Sci. 66, 3289–3307 (2009). https://doi.org/10.1007/s00018-009-0086-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-009-0086-3

Keywords

Search

Navigation