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PMID: 25313309 Published · ppublish English Journal Article Review

p38δ MAPK: Emerging Roles of a Neglected Isoform.

International journal of cell biology ·Vol. 2014 ·2014-00-00 ·Pages 272689

O'Callaghan C, Fanning LJ, Barry OP

Abstract

p38δ mitogen activated protein kinase (MAPK) is a unique stress responsive protein kinase. While the p38 MAPK family as a whole has been implicated in a wide variety of biological processes, a specific role for p38δ MAPK in cellular signalling and its contribution to both physiological and pathological conditions are presently lacking. Recent emerging evidence, however, provides some insights into specific p38δ MAPK signalling. Importantly, these studies have helped to highlight functional similarities as well as differences between p38δ MAPK and the other members of the p38 MAPK family of kinases. In this review we discuss the current understanding of the molecular mechanisms underlying p38δ MAPK activity. We outline a role for p38δ MAPK in important cellular processes such as differentiation and apoptosis as well as pathological conditions such as neurodegenerative disorders, diabetes, and inflammatory disease. Interestingly, disparate roles for p38δ MAPK in tumour development have also recently been reported. Thus, we consider evidence which characterises p38δ MAPK as both a tumour promoter and a tumour suppressor. In summary, while our knowledge of p38δ MAPK has progressed somewhat since its identification in 1997, our understanding of this particular isoform in many cellular processes still strikingly lags behind that of its counterparts.

Authors & Affiliations
3 authors, click to expand affiliations / ORCID
O'Callaghan Carol
Department of Pharmacology and Therapeutics, Western Gateway Building, Western Road, University College Cork, Cork, Ireland.
Fanning Liam J
Molecular Virology Diagnostic & Research Laboratory, Department of Medicine, Clinical Sciences Building, University College Cork and Cork University Hospital, Cork, Ireland.
Barry Orla P
Department of Pharmacology and Therapeutics, Western Gateway Building, Western Road, University College Cork, Cork, Ireland.
References (110)
110 references, click to expand
  1. A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta.
    EMBO J. 2001 Aug 15;20(16):4360-9 PMID: 11500363
  2. Activation of PKCdelta and p38delta MAPK during okadaic acid dependent keratinocyte apoptosis.
    Arch Dermatol Res. 2007 May;299(2):71-83 PMID: 17256148
  3. Cholesterol depletion upregulates involucrin expression in epidermal keratinocytes through activation of p38.
    J Invest Dermatol. 2004 Sep;123(3):564-73 PMID: 15304097
  4. 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):7420-6 PMID: 7535770
  5. The life and death of translation elongation factor 2.
    Biochem Soc Trans. 2006 Feb;34(Pt 1):1-6 PMID: 16246167
  6. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways.
    Science. 1997 Jan 3;275(5296):90-4 PMID: 8974401
  7. Evidence of p38γ and p38δ involvement in cell transformation processes.
    Carcinogenesis. 2011 Jul;32(7):1093-9 PMID: 21558321
  8. MKP-1 inhibits high NaCl-induced activation of p38 but does not inhibit the activation of TonEBP/OREBP: opposite roles of p38alpha and p38delta.
    Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5620-5 PMID: 18367666
  9. 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):3563-71 PMID: 9218798
  10. Epidermal differentiation, apoptosis, and senescence: common pathways?
    Exp Gerontol. 2000 Feb;35(1):53-62 PMID: 10705039
  11. p38MAPK delta controls c-Myb degradation in response to stress.
    Blood Cells Mol Dis. 2008 May-Jun;40(3):388-94 PMID: 18006338
  12. Acceleration of bone repair in NOD/SCID mice by human monoosteophils, novel LL-37-activated monocytes.
    PLoS One. 2013 Jul 03;8(7):e67649 PMID: 23844045
  13. Feedback control of the protein kinase TAK1 by SAPK2a/p38alpha.
    EMBO J. 2003 Nov 3;22(21):5793-805 PMID: 14592977
  14. Stathmin: a tubulin-sequestering protein which forms a ternary T2S complex with two tubulin molecules.
    Biochemistry. 1997 Sep 9;36(36):10817-21 PMID: 9312271
  15. Characterization of airway plugging in fatal asthma.
    Am J Med. 2003 Jul;115(1):6-11 PMID: 12867228
  16. Hallmarks of cancer: the next generation.
    Cell. 2011 Mar 4;144(5):646-74 PMID: 21376230
  17. p38(MAPK): stress responses from molecular mechanisms to therapeutics.
    Trends Mol Med. 2009 Aug;15(8):369-79 PMID: 19665431
  18. Acquisition of sensitivity of stress-activated protein kinases to the p38 inhibitor, SB 203580, by alteration of one or more amino acids within the ATP binding pocket.
    J Biol Chem. 1998 Jun 19;273(25):15605-10 PMID: 9624152
  19. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells.
    Science. 1994 Aug 5;265(5173):808-11 PMID: 7914033
  20. p38 Mitogen-activated protein kinases on the body surface--a function for p38 delta.
    J Invest Dermatol. 2003 May;120(5):823-8 PMID: 12713588
  21. Neurodegenerative tauopathies.
    Annu Rev Neurosci. 2001;24:1121-59 PMID: 11520930
  22. The mitogen-activated protein kinases p38 and ERK1/2 are increased in lesional psoriatic skin.
    Br J Dermatol. 2005 Jan;152(1):37-42 PMID: 15656798
  23. Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases.
    FEBS Lett. 1997 Jun 2;409(1):57-62 PMID: 9199504
  24. The acute respiratory distress syndrome.
    N Engl J Med. 2000 May 4;342(18):1334-49 PMID: 10793167
  25. p38delta Mitogen-activated protein kinase is essential for skin tumor development in mice.
    Cancer Res. 2009 Jun 1;69(11):4648-55 PMID: 19458068
  26. Interleukin-13: central mediator of allergic asthma.
    Science. 1998 Dec 18;282(5397):2258-61 PMID: 9856949
  27. p44 mitogen-activated protein kinase (extracellular signal-regulated kinase 1)-dependent signaling contributes to epithelial skin carcinogenesis.
    Cancer Res. 2006 Mar 1;66(5):2700-7 PMID: 16510590
  28. Hyperactive variants of p38alpha induce, whereas hyperactive variants of p38gamma suppress, activating protein 1-mediated transcription.
    J Biol Chem. 2007 Jan 5;282(1):91-9 PMID: 17088247
  29. CXCL12 and C5a trigger cell migration via a PAK1/2-p38alpha MAPK-MAPKAP-K2-HSP27 pathway.
    Cell Signal. 2006 Nov;18(11):1897-905 PMID: 16574378
  30. Brain-metastatic triple-negative breast cancer cells regain growth ability by altering gene expression patterns.
    Cancer Genomics Proteomics. 2013 Nov-Dec;10(6):265-75 PMID: 24336635
  31. Loss of p38δ mitogen-activated protein kinase expression promotes oesophageal squamous cell carcinoma proliferation, migration and anchorage-independent growth.
    Int J Oncol. 2013 Aug;43(2):405-15 PMID: 23722928
  32. MEK6 regulates human involucrin gene expression via a p38alpha - and p38delta -dependent mechanism.
    J Biol Chem. 2001 Jul 20;276(29):27214-20 PMID: 11454875
  33. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation.
    Physiol Rev. 2001 Apr;81(2):807-69 PMID: 11274345
  34. Role of mitogen-activated protein kinase kinase kinases in signal integration.
    Oncogene. 2007 May 14;26(22):3159-71 PMID: 17496913
  35. MAPKK-independent activation of p38alpha mediated by TAB1-dependent autophosphorylation of p38alpha.
    Science. 2002 Feb 15;295(5558):1291-4 PMID: 11847341
  36. The stathmin/tubulin interaction in vitro.
    J Biol Chem. 1997 Oct 3;272(40):25029-36 PMID: 9312110
  37. p38gamma regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP.
    EMBO J. 2005 Mar 23;24(6):1134-45 PMID: 15729360
  38. Novel homologues of CSBP/p38 MAP kinase: activation, substrate specificity and sensitivity to inhibition by pyridinyl imidazoles.
    Biochem Biophys Res Commun. 1997 Jun 27;235(3):533-8 PMID: 9207191
  39. A Novel MAPK phosphatase MKP-7 acts preferentially on JNK/SAPK and p38 alpha and beta MAPKs.
    J Biol Chem. 2001 Jul 13;276(28):26629-39 PMID: 11359773
  40. Signal transducer and activator of transcription 3 (Stat3) in epithelial carcinogenesis.
    Mol Carcinog. 2007 Aug;46(8):725-31 PMID: 17610223
  41. Mixed-lineage kinase control of JNK and p38 MAPK pathways.
    Nat Rev Mol Cell Biol. 2002 Sep;3(9):663-72 PMID: 12209126
  42. Alternative p38 MAPKs are essential for collagen-induced arthritis.
    Arthritis Rheumatol. 2014 May;66(5):1208-17 PMID: 24782184
  43. New Insights into the p38γ and p38δ MAPK Pathways.
    J Signal Transduct. 2012;2012:520289 PMID: 22175015
  44. Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta).
    J Biol Chem. 1996 Jul 26;271(30):17920-6 PMID: 8663524
  45. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease.
    Nat Med. 2008 Jun;14(6):633-40 PMID: 18488036
  46. Roles of p38 MAPKs in invasion and metastasis.
    Biochem Soc Trans. 2012 Feb;40(1):79-84 PMID: 22260669
  47. Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding.
    Neuron. 1993 Jun;10(6):1089-99 PMID: 8318230
  48. The significance of tau and alpha-synuclein inclusions in neurodegenerative diseases.
    Curr Opin Genet Dev. 2001 Jun;11(3):343-51 PMID: 11377973
  49. Differential expression and activation of p38 mitogen-activated protein kinase alpha, beta, gamma, and delta in inflammatory cell lineages.
    J Immunol. 1999 Apr 1;162(7):4246-52 PMID: 10201954
  50. The primary structure of p38 gamma: a new member of p38 group of MAP kinases.
    Biochem Biophys Res Commun. 1996 Nov 12;228(2):334-40 PMID: 8920915
  51. Novel protein kinase C isoforms regulate human keratinocyte differentiation by activating a p38 delta mitogen-activated protein kinase cascade that targets CCAAT/enhancer-binding protein alpha.
    J Biol Chem. 2002 Aug 30;277(35):31753-60 PMID: 12080077
  52. Delayed cell cycle progression in selenoprotein W-depleted cells is regulated by a mitogen-activated protein kinase kinase 4-p38/c-Jun NH2-terminal kinase-p53 pathway.
    J Biol Chem. 2012 Aug 10;287(33):27371-9 PMID: 22730327
  53. Mitogen-activated protein kinase p38 mediates reduced nerve conduction velocity in experimental diabetic neuropathy: interactions with aldose reductase.
    Diabetes. 2004 Jul;53(7):1851-6 PMID: 15220210
  54. MEK7-dependent activation of p38 MAP kinase in keratinocytes.
    J Biol Chem. 2001 Mar 16;276(11):8059-63 PMID: 11244091
  55. Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion.
    Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9827-32 PMID: 10449779
  56. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1.
    FEBS Lett. 1995 May 8;364(2):229-33 PMID: 7750577
  57. Evidence that cytokines play a role in rheumatoid arthritis.
    J Clin Invest. 2008 Nov;118(11):3537-45 PMID: 18982160
  58. A regulatory role for p38 delta MAPK in keratinocyte differentiation. Evidence for p38 delta-ERK1/2 complex formation.
    J Biol Chem. 2003 Sep 5;278(36):34277-85 PMID: 12810719
  59. Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator Pak1.
    J Biol Chem. 1995 Oct 13;270(41):23934-6 PMID: 7592586
  60. MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines.
    Genes Dev. 2001 Jun 1;15(11):1419-26 PMID: 11390361
  61. Molecular cloning and characterization of a novel p38 mitogen-activated protein kinase.
    J Biol Chem. 1997 Sep 19;272(38):23668-74 PMID: 9295308
  62. A highly specific inhibitor of human p38 MAP kinase binds in the ATP pocket.
    Nat Struct Biol. 1997 Apr;4(4):311-6 PMID: 9095200
  63. Murine p38-delta mitogen-activated protein kinase, a developmentally regulated protein kinase that is activated by stress and proinflammatory cytokines.
    J Biol Chem. 1999 Mar 12;274(11):7095-102 PMID: 10066767
  64. Mechanisms and functions of p38 MAPK signalling.
    Biochem J. 2010 Aug 1;429(3):403-17 PMID: 20626350
  65. Genome-wide screen of promoter methylation identifies novel markers in melanoma.
    Genome Res. 2009 Aug;19(8):1462-70 PMID: 19491193
  66. A network of mitogen-activated protein kinases links G protein-coupled receptors to the c-jun promoter: a role for c-Jun NH2-terminal kinase, p38s, and extracellular signal-regulated kinase 5.
    Mol Cell Biol. 1999 Jun;19(6):4289-301 PMID: 10330170
  67. p38δ MAPK phenotype: an indicator of chemotherapeutic response in oesophageal squamous cell carcinoma.
    Anticancer Drugs. 2015 Jan;26(1):46-55 PMID: 25099621
  68. p38 MAP kinase's emerging role as a tumor suppressor.
    Adv Cancer Res. 2004;92:95-118 PMID: 15530558
  69. Green tea polyphenol stimulates a Ras, MEKK1, MEK3, and p38 cascade to increase activator protein 1 factor-dependent involucrin gene expression in normal human keratinocytes.
    J Biol Chem. 2002 Jan 18;277(3):1828-36 PMID: 11698415
  70. Genome-wide promoter methylation analysis identifies epigenetic silencing of MAPK13 in primary cutaneous melanoma.
    Pigment Cell Melanoma Res. 2013 Jul;26(4):542-54 PMID: 23590314
  71. Generation and characterization of p38beta (MAPK11) gene-targeted mice.
    Mol Cell Biol. 2005 Dec;25(23):10454-64 PMID: 16287858
  72. p38alpha: a suppressor of cell proliferation and tumorigenesis.
    Cell Cycle. 2007 Oct 15;6(20):2429-33 PMID: 17957136
  73. Differential tissue expression and activation of p38 MAPK alpha, beta, gamma, and delta isoforms in rheumatoid arthritis.
    Arthritis Rheum. 2006 Sep;54(9):2745-56 PMID: 16947383
  74. Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis.
    J Clin Invest. 2004 Sep;114(5):720-8 PMID: 15343391
  75. New functions for the matrix metalloproteinases in cancer progression.
    Nat Rev Cancer. 2002 Mar;2(3):161-74 PMID: 11990853
  76. Synergistic activation of SAPK1/JNK1 by two MAP kinase kinases in vitro.
    Curr Biol. 1998 Dec 17-31;8(25):1387-90 PMID: 9889102
  77. Eukaryotic elongation factor 2 controls TNF-α translation in LPS-induced hepatitis.
    J Clin Invest. 2013 Jan;123(1):164-78 PMID: 23202732
  78. Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction.
    Science. 1995 Dec 22;270(5244):2008-11 PMID: 8533096
  79. BIRB796 inhibits all p38 MAPK isoforms in vitro and in vivo.
    J Biol Chem. 2005 May 20;280(20):19472-9 PMID: 15755732
  80. Epigenetic profiles distinguish malignant pleural mesothelioma from lung adenocarcinoma.
    Cancer Res. 2009 Dec 1;69(23):9073-82 PMID: 19887624
  81. p38 MAP-kinases pathway regulation, function and role in human diseases.
    Biochim Biophys Acta. 2007 Aug;1773(8):1358-75 PMID: 17481747
  82. p38alpha MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation.
    Nat Genet. 2007 Jun;39(6):750-8 PMID: 17468755
  83. Intrinsically active variants of all human p38 isoforms.
    FEBS J. 2007 Feb;274(4):963-75 PMID: 17241234
  84. Evolutionary history of the vertebrate mitogen activated protein kinases family.
    PLoS One. 2011;6(10):e26999 PMID: 22046431
  85. An osmosensing signal transduction pathway in yeast.
    Science. 1993 Mar 19;259(5102):1760-3 PMID: 7681220
  86. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis.
    Nature. 1994 Dec 22-29;372(6508):739-46 PMID: 7997261
  87. Differentiation stage-specific activation of p38 mitogen-activated protein kinase isoforms in primary human erythroid cells.
    Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):147-52 PMID: 14694199
  88. p38delta mitogen-activated protein kinase regulates skin homeostasis and tumorigenesis.
    Cell Cycle. 2010 Feb 1;9(3):498-05 PMID: 20090411
  89. Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for activation of p38alpha and p38delta MAPK isoforms by TGF-beta 1 in murine mesangial cells.
    J Biol Chem. 2002 Dec 6;277(49):47257-62 PMID: 12374793
  90. Protein kinase Cdelta regulates keratinocyte death and survival by regulating activity and subcellular localization of a p38delta-extracellular signal-regulated kinase 1/2 complex.
    Mol Cell Biol. 2004 Sep;24(18):8167-83 PMID: 15340077
  91. 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):1027-37 PMID: 7923353
  92. Fibroblast growth factor homologous factors and the islet brain-2 scaffold protein regulate activation of a stress-activated protein kinase.
    J Biol Chem. 2002 Dec 20;277(51):49111-9 PMID: 12244047
  93. Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases.
    Nat Immunol. 2005 Apr;6(4):390-5 PMID: 15735648
  94. p38δ mitogen-activated protein kinase regulates the expression of tight junction protein ZO-1 in differentiating human epidermal keratinocytes.
    Arch Dermatol Res. 2014 Mar;306(2):131-41 PMID: 23856837
  95. p38delta/MAPK13 as a diagnostic marker for cholangiocarcinoma and its involvement in cell motility and invasion.
    Int J Cancer. 2010 May 15;126(10):2353-61 PMID: 19816939
  96. Forced expression of a constitutively active form of Stat3 in mouse epidermis enhances malignant progression of skin tumors induced by two-stage carcinogenesis.
    Oncogene. 2008 Feb 14;27(8):1087-94 PMID: 17700521
  97. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.
    Physiol Rev. 2012 Apr;92(2):689-737 PMID: 22535895
  98. Differential activation of p38MAPK isoforms by MKK6 and MKK3.
    Cell Signal. 2010 Apr;22(4):660-7 PMID: 20004242
  99. p38alpha and p38delta mitogen-activated protein kinase isoforms regulate invasion and growth of head and neck squamous carcinoma cells.
    Oncogene. 2007 Aug 9;26(36):5267-79 PMID: 17334397
  100. Conversion of SB 203580-insensitive MAP kinase family members to drug-sensitive forms by a single amino-acid substitution.
    Chem Biol. 1998 Jun;5(6):321-8 PMID: 9653550
  101. Regulation of PTEN activity by p38δ-PKD1 signaling in neutrophils confers inflammatory responses in the lung.
    J Exp Med. 2012 Nov 19;209(12):2229-46 PMID: 23129748
  102. Genomic analysis defines a cancer-specific gene expression signature for human squamous cell carcinoma and distinguishes malignant hyperproliferation from benign hyperplasia.
    J Invest Dermatol. 2006 Apr;126(4):869-81 PMID: 16470182
  103. 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):30122-8 PMID: 9374491
  104. Renal p38 MAP kinase activity in experimental diabetes.
    Lab Invest. 2007 Jun;87(6):548-58 PMID: 17401436
  105. Identification of stathmin as a novel substrate for p38 delta.
    Biochem Biophys Res Commun. 1998 Aug 28;249(3):791-6 PMID: 9731215
  106. Regulation of PKD by the MAPK p38delta in insulin secretion and glucose homeostasis.
    Cell. 2009 Jan 23;136(2):235-48 PMID: 19135240
  107. IL-13-induced airway mucus production is attenuated by MAPK13 inhibition.
    J Clin Invest. 2012 Dec;122(12):4555-68 PMID: 23187130
  108. Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27.
    Cell. 1994 Sep 23;78(6):1039-49 PMID: 7923354
  109. Impaired synergistic activation of stress-activated protein kinase SAPK/JNK in mouse embryonic stem cells lacking SEK1/MKK4: different contribution of SEK2/MKK7 isoforms to the synergistic activation.
    J Biol Chem. 2001 Aug 17;276(33):30892-7 PMID: 11418587
  110. Deficiency of the stress kinase p38alpha results in embryonic lethality: characterization of the kinase dependence of stress responses of enzyme-deficient embryonic stem cells.
    J Exp Med. 2000 Mar 6;191(5):859-70 PMID: 10704466
Article Info
Journal
International journal of cell biology
Abbr.
Int J Cell Biol
ISSN
1687-8876
DOI
10.1155/2014/272689
Published
2014-00-00
Epub
2014-00-17
Pages
272689
Language
English
Region
United States
NLM ID
101517861
PMCID
PMC4182853
External Links
PubMed source DOI: 10.1155/2014/272689 PMC Full Text
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