In the Cellular Garden of Forking Paths: How p38 MAPKs Signal for Downstream Assistance

Abstract Mitogenactivated protein kinases (MAPKs) are evolutionarily conserved enzymes which connect cellsurface receptors to regulatory targets within cells and convert receptor signals into various outputs. In mammalian cells, four distinct MAPKs have been identified: the extracellular signalrelated kinases (ERK)-1/2, the cjun Nterminal kinases or stressactivated protein kinases 1 (JNK1/2/3, or SAPK1s), the p38 MAPKs (p38 α/β/γ/δ, or SAPK2s), and the ERK5 or big MAP kinase 1 (BMK1). The p38 MAPK cascade is activated by stress or cytokines and leads to phosphorylation of its central elements, the p38 MAPKs. Downstream of p38 MAPKs there is a diversification and extensive branching of signalling pathways. For that reason, we will focus in this review on the different signalling events that are triggered by p38 activity, and analyse how these events contribute to specific gene expression and cellular responses.

[1]  E. Winter,et al.  An osmosensing signal transduction pathway in yeast. , 1993, Science.

[2]  David Stokoe,et al.  Identification of MAPKAP kinase 2 as a major enzyme responsible for the phosphorylation of the small mammalian heat shock proteins , 1992, FEBS letters.

[3]  H. Gram,et al.  Negative Regulation of Protein Translation by Mitogen-Activated Protein Kinase-Interacting Kinases 1 and 2 , 2001, Molecular and Cellular Biology.

[4]  J. Landry,et al.  Regulation of actin filament dynamics by p38 map kinase-mediated phosphorylation of heat shock protein 27. , 1997, Journal of cell science.

[5]  A. Zaheer,et al.  Overexpression of glia maturation factor (GMF) in PC12 pheochromocytoma cells activates p38 MAP kinase, MAPKAP kinase-2, and tyrosine hydroxylase. , 1998, Biochemical and biophysical research communications.

[6]  S. Saccani,et al.  p38-dependent marking of inflammatory genes for increased NF-κB recruitment , 2002, Nature Immunology.

[7]  J Ross,et al.  Cardiac Muscle Cell Hypertrophy and Apoptosis Induced by Distinct Members of the p38 Mitogen-activated Protein Kinase Family* , 1998, The Journal of Biological Chemistry.

[8]  L Bibbs,et al.  A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. , 1994, Science.

[9]  Jonathan A. Cooper,et al.  The Phosphorylation of Eukaryotic Initiation Factor eIF4E in Response to Phorbol Esters, Cell Stresses, and Cytokines Is Mediated by Distinct MAP Kinase Pathways* , 1998, The Journal of Biological Chemistry.

[10]  W. Li,et al.  The p38-MAPK/SAPK pathway is required for human keratinocyte migration on dermal collagen. , 2001, The Journal of investigative dermatology.

[11]  B. Foxwell,et al.  The Pyridinyl Imidazole Inhibitor SB203580 Blocks Phosphoinositide-dependent Protein Kinase Activity, Protein Kinase B Phosphorylation, and Retinoblastoma Hyperphosphorylation in Interleukin-2-stimulated T Cells Independently of p38 Mitogen-activated Protein Kinase* , 2000, The Journal of Biological Chemistry.

[12]  N. Sonenberg,et al.  Phosphorylation of Eukaryotic Translation Initiation Factor 4E Is Critical for Growth , 2002, Molecular and Cellular Biology.

[13]  K. Wilson,et al.  A single amino acid substitution makes ERK2 susceptible to pyridinyl imidazole inhibitors of p38 MAP kinase , 1998, Protein science : a publication of the Protein Society.

[14]  A. Clerk,et al.  Stimulation of the p38 Mitogen-activated Protein Kinase Pathway in Neonatal Rat Ventricular Myocytes by the G Protein–coupled Receptor Agonists, Endothelin-1 and Phenylephrine: A Role in Cardiac Myocyte Hypertrophy? , 1998, The Journal of cell biology.

[15]  A. Gingras,et al.  Regulation of translation initiation by FRAP/mTOR. , 2001, Genes & development.

[16]  Chi‐Kuang Huang,et al.  Characterization of an Autoinhibitory Domain in Human Mitogen-activated Protein Kinase-activated Protein Kinase 2 (*) , 1995, The Journal of Biological Chemistry.

[17]  P. Blackshear,et al.  Feedback Inhibition of Macrophage Tumor Necrosis Factor-α Production by Tristetraprolin , 1998 .

[18]  O. Volpert,et al.  Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1 , 2000, Nature Medicine.

[19]  J. Pouysségur,et al.  Cyclin D1 Expression Is Regulated Positively by the p42/p44MAPK and Negatively by the p38/HOGMAPK Pathway* , 1996, The Journal of Biological Chemistry.

[20]  V. Erdmann,et al.  Identification of the phosphorylation sites of the murine small heat shock protein hsp25. , 1991, The Journal of biological chemistry.

[21]  C. Ambrosino,et al.  Cell cycle regulation by p38 MAP kinases , 2001, Biology of the cell.

[22]  J. Ihle.  The Challenges of Translating Knockout Phenotypes into Gene Function , 2000, Cell.

[23]  P. Young,et al.  Identification of two distinct regions of p38 MAPK required for substrate binding and phosphorylation. , 1999, Biochemical and biophysical research communications.

[24]  L. Zon,et al.  Cdc42Hs, but Not Rac1, Inhibits Serum-stimulated Cell Cycle Progression at G1/S through a Mechanism Requiring p38/RK* , 1997, The Journal of Biological Chemistry.

[25]  K. Mahtani,et al.  Mitogen-Activated Protein Kinase p38 Controls the Expression and Posttranslational Modification of Tristetraprolin, a Regulator of Tumor Necrosis Factor Alpha mRNA Stability , 2001, Molecular and Cellular Biology.

[26]  M. Morange,et al.  Hsp25 and the p38 MAPK pathway are involved in differentiation of cardiomyocytes. , 2000, Developmental biology.

[27]  M. Dickens,et al.  c-Myc Protein Synthesis Is Initiated from the Internal Ribosome Entry Segment during Apoptosis , 2000, Molecular and Cellular Biology.

[28]  J. Behlke,et al.  Phosphorylation and supramolecular organization of murine small heat shock protein HSP25 abolish its actin polymerization-inhibiting activity. , 1994, The Journal of biological chemistry.

[29]  K. Mahtani,et al.  The 3′ Untranslated Region of Tumor Necrosis Factor Alpha mRNA Is a Target of the mRNA-Stabilizing Factor HuR , 2001, Molecular and Cellular Biology.

[30]  J. Minna,et al.  3pK, a new mitogen-activated protein kinase-activated protein kinase located in the small cell lung cancer tumor suppressor gene region , 1996, Molecular and cellular biology.

[31]  E. Nishida,et al.  A Novel MAPK Phosphatase MKP-7 Acts Preferentially on JNK/SAPK and p38α and β MAPKs* , 2001, The Journal of Biological Chemistry.

[32]  P. Cohen,et al.  Effects of the inhibition of p38/RK MAP kinase on induction of five fos and jun genes by diverse stimuli , 1997, Oncogene.

[33]  Jiahuai Han,et al.  Regulation of the MEF2 Family of Transcription Factors by p38 , 1999, Molecular and Cellular Biology.

[34]  Francisco Diaz-Mitoma,et al.  The p38 Mitogen-activated Kinase Pathway Regulates the Human Interleukin-10 Promoter via the Activation of Sp1 Transcription Factor in Lipopolysaccharide-stimulated Human Macrophages* , 2001, The Journal of Biological Chemistry.

[35]  H. Enslen,et al.  Molecular determinants that mediate selective activation of p38 MAP kinase isoforms , 2000, The EMBO journal.

[36]  U. Rapp,et al.  Serine/Threonine Kinases 3pK and MAPK-activated Protein Kinase 2 Interact with the Basic Helix-Loop-Helix Transcription Factor E47 and Repress Its Transcriptional Activity* , 2000, The Journal of Biological Chemistry.

[37]  P. Plinkert,et al.  The p38 SAPK pathway regulates the expression of the MMP-9 collagenase via AP-1-dependent promoter activation. , 2001, Experimental cell research.

[38]  I. Mellman,et al.  Defective IL‐12 production in mitogen‐activated protein (MAP) kinase kinase 3 (Mkk3)‐deficient mice , 1999, The EMBO journal.

[39]  Annette Gilchrist,et al.  p38 mitogen-activated protein kinase activation is required for human neutrophil function triggered by TNF-alpha or FMLP stimulation. , 1998, Journal of immunology.

[40]  S. Zhuang,et al.  p38 Mitogen-activated Protein Kinase Mediates Bid Cleavage, Mitochondrial Dysfunction, and Caspase-3 Activation during Apoptosis Induced by Singlet Oxygen but Not by Hydrogen Peroxide* , 2000, The Journal of Biological Chemistry.

[41]  M. Gaestel,et al.  Distinct Cellular Functions of MK2 , 2002, Molecular and Cellular Biology.

[42]  A. Lustig,et al.  The Function of the NC1 Domains in Type IV Collagen (*) , 1995, The Journal of Biological Chemistry.

[43]  S. Carreira,et al.  The Usf‐1 transcription factor is a novel target for the stress‐responsive p38 kinase and mediates UV‐induced Tyrosinase expression , 2001, The EMBO journal.

[44]  W. Lesslauer,et al.  RSK-B, a Novel Ribosomal S6 Kinase Family Member, Is a CREB Kinase under Dominant Control of p38α Mitogen-activated Protein Kinase (p38αMAPK)* , 1998, The Journal of Biological Chemistry.

[45]  P. Cohen,et al.  Activation of the MAP kinase homologue RK requires the phosphorylation of Thr‐180 and Tyr‐182 and both residues are phosphorylated in chemically stressed KB cells , 1995, FEBS letters.

[46]  P. Cohen,et al.  Specificity and mechanism of action of some commonly used protein kinase inhibitors. , 2000, The Biochemical journal.

[47]  P. Cohen,et al.  Stress-activated Protein Kinase-2/p38 and a Rapamycin-sensitive Pathway Are Required for C2C12 Myogenesis* , 1999, The Journal of Biological Chemistry.

[48]  Jonathan A. Cooper,et al.  Mitogen‐activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2 , 1997, The EMBO journal.

[49]  Weiya Ma,et al.  p38 Kinase Mediates UV-induced Phosphorylation of p53 Protein at Serine 389* , 1999, The Journal of Biological Chemistry.

[50]  Philip R. Cohen,et al.  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 , 1997, The EMBO journal.

[51]  E. Nishida,et al.  Activation of the protein kinase p38 in the spindle assembly checkpoint and mitotic arrest. , 1998, Science.

[52]  M. Gaestel,et al.  MAPKAP kinase 2 is essential for LPS-induced TNF-α biosynthesis , 1999, Nature Cell Biology.

[53]  Tony Hunter,et al.  MNK1, a new MAP kinase‐activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates , 1997, The EMBO journal.

[54]  J. Pouysségur,et al.  The p42/p44 Mitogen-activated Protein Kinase Cascade Is Determinant in Mediating Activation of the Na+/H+ Exchanger (NHE1 Isoform) in Response to Growth Factors* , 1997, The Journal of Biological Chemistry.

[55]  Xuechu Zhen,et al.  Mitogen-activated Protein Kinase p38 Mediates Regulation of Chondrocyte Differentiation by Parathyroid Hormone* , 2001, The Journal of Biological Chemistry.

[56]  Yong Jiang,et al.  PRAK, a novel protein kinase regulated by the p38 MAP kinase , 1998, The EMBO journal.

[57]  E. Levin,et al.  Heat shock protein 27 kDa expression and phosphorylation regulates endothelial cell migration , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[58]  A. Ullrich,et al.  ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[59]  P. Cohen,et al.  Serine 727 Phosphorylation and Activation of Cytosolic Phospholipase A2 by MNK1-related Protein Kinases* , 2000, The Journal of Biological Chemistry.

[60]  L. Tong,et al.  A highly specific inhibitor of human p38 MAP kinase binds in the ATP pocket , 1997, Nature Structural Biology.

[61]  John C. Lee,et al.  Identification of Mitogen-activated Protein (MAP) Kinase-activated Protein Kinase-3, a Novel Substrate of CSBP p38 MAP Kinase (*) , 1996, The Journal of Biological Chemistry.

[62]  U. Greber,et al.  Adenovirus‐activated PKA and p38/MAPK pathways boost microtubule‐mediated nuclear targeting of virus , 2001, The EMBO journal.

[63]  O. Werz,et al.  Arachidonic Acid Promotes Phosphorylation of 5-Lipoxygenase at Ser-271 by MAPK-activated Protein Kinase 2 (MK2)* , 2002, The Journal of Biological Chemistry.

[64]  M. Gelb,et al.  Identification of the Phosphorylation Sites of Cytosolic Phospholipase A2 in Agonist-stimulated Human Platelets and HeLa Cells* , 1998, The Journal of Biological Chemistry.

[65]  Taro Matsumoto,et al.  p38 MAP kinase negatively regulates endothelial cell survival, proliferation, and differentiation in FGF-2–stimulated angiogenesis , 2002, The Journal of cell biology.

[66]  M. Gaestel,et al.  The MAP kinase‐activated protein kinase 2 contains a proline‐rich SH3‐binding domain , 1993, FEBS letters.

[67]  R. Klein,et al.  Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development. , 2000, Molecular cell.

[68]  E. Appella,et al.  Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase , 2001, Nature.

[69]  T. Hunter,et al.  Convergence of MAP kinase pathways on the ternary complex factor Sap‐1a , 1997, The EMBO journal.

[70]  C. Anderson,et al.  Human HSP27 is phosphorylated at serines 78 and 82 by heat shock and mitogen-activated kinases that recognize the same amino acid motif as S6 kinase II. , 1992, The Journal of biological chemistry.

[71]  J. Saklatvala,et al.  Regulation of tumour necrosis factor α mRNA stability by the mitogen‐activated protein kinase p38 signalling cascade , 2000, FEBS letters.

[72]  L. Zon,et al.  Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis , 1996, Nature.

[73]  Philip R. Cohen,et al.  SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin‐1 , 1995, FEBS letters.

[74]  John C. Lee,et al.  p38 mitogen activated protein kinase regulates endothelial VCAM-1 expression at the post-transcriptional level. , 1997, Biochemical and biophysical research communications.

[75]  M. Gaestel,et al.  3pK, a novel mitogen-activated protein (MAP) kinase-activated protein kinase, is targeted by three MAP kinase pathways , 1996, Molecular and cellular biology.

[76]  L. Mahadevan,et al.  Combinations of ERK and p38 MAPK Inhibitors Ablate Tumor Necrosis Factor-α (TNF-α) mRNA Induction , 2001, The Journal of Biological Chemistry.

[77]  K. Irie,et al.  The Drosophila p38 MAPK pathway is required during oogenesis for egg asymmetric development. , 1999, Genes & development.

[78]  Steven A. Carr,et al.  Pyridinyl Imidazole Inhibitors of p38 Mitogen-activated Protein Kinase Bind in the ATP Site* , 1997, The Journal of Biological Chemistry.

[79]  K. Muegge,et al.  Trophic Factor Withdrawal: p38 Mitogen-Activated Protein Kinase Activates NHE1, Which Induces Intracellular Alkalinization , 2001, Molecular and Cellular Biology.

[80]  Y. Nagamine,et al.  Regulation by p38 mitogen-activated protein kinase of adenylate- and uridylate-rich element-mediated urokinase-type plasminogen activator (uPA) messenger RNA stability and uPA-dependent in vitro cell invasion. , 1999, Cancer research.

[81]  K. Heidenreich,et al.  Inhibition of p38 Mitogen-activated Protein Kinase by Insulin in Cultured Fetal Neurons (*) , 1996, The Journal of Biological Chemistry.

[82]  P. Blackshear,et al.  Decreased Sensitivity of Tristetraprolin-deficient Cells to p38 Inhibitors Suggests the Involvement of Tristetraprolin in the p38 Signaling Pathway* , 2001, The Journal of Biological Chemistry.

[83]  P. Cohen,et al.  Stress-induced phosphorylation of STAT1 at Ser727 requires p38 mitogen-activated protein kinase whereas IFN-gamma uses a different signaling pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[84]  R. Flavell,et al.  Activation of the p38 Mitogen-Activated Protein Kinase Pathway Arrests Cell Cycle Progression and Differentiation of Immature Thymocytes in Vivo , 2000, The Journal of experimental medicine.

[85]  M. Su,et al.  Interferon‐γ expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway , 1998, The EMBO journal.

[86]  J. Lee,et al.  Inhibition of prostaglandin endoperoxide synthase-2 expression in stimulated human monocytes by inhibitors of p38 mitogen-activated protein kinase. , 1997, Journal of immunology.

[87]  S K Burley,et al.  Hierarchical phosphorylation of the translation inhibitor 4E-BP1. , 2001, Genes & development.

[88]  R. Aebersold,et al.  Regulation of the Meiosis-inhibited Protein Kinase, a p38MAPK Isoform, During Meiosis and Following Fertilization of Seastar Oocytes* , 2000, The Journal of Biological Chemistry.

[89]  P. Lograsso,et al.  Signalling for survival and death in neurones: the role of stress-activated kinases, JNK and p38. , 2001, Cellular signalling.

[90]  W. Sessa,et al.  Akt Down-regulation of p38 Signaling Provides a Novel Mechanism of Vascular Endothelial Growth Factor-mediated Cytoprotection in Endothelial Cells* , 2001, The Journal of Biological Chemistry.

[91]  E. Nishida,et al.  Requirement of p38 Mitogen-activated Protein Kinase for Neuronal Differentiation in PC12 Cells* , 1998, The Journal of Biological Chemistry.

[92]  H. Enslen,et al.  T Cells + but Not CD 4 + Apoptosis of CD 8 Kinase In Vivo Selectively Induces Activation of p 38 Mitogen-Activated Protein , 1999 .

[93]  J. Dean,et al.  p38 Mitogen-activated Protein Kinase Regulates Cyclooxygenase-2 mRNA Stability and Transcription in Lipopolysaccharide-treated Human Monocytes* , 1999, The Journal of Biological Chemistry.

[94]  M. Gaestel,et al.  Leptomycin B‐sensitive nuclear export of MAPKAP kinase 2 is regulated by phosphorylation , 1998, The EMBO journal.

[95]  Philip R. Cohen,et al.  Use of a drug‐resistant mutant of stress‐activated protein kinase 2a/p38 to validate the in vivo specificity of SB 203580 , 1999, FEBS letters.

[96]  M. Su,et al.  Role of p38 and JNK mitogen-activated protein kinases in the activation of ternary complex factors , 1997, Molecular and cellular biology.

[97]  T. Hyypiä,et al.  Echovirus 1 infection induces both stress- and growth-activated mitogen-activated protein kinase pathways and regulates the transcription of cellular immediate-early genes. , 1998, Virology.

[98]  Jiahuai Han,et al.  MAPKK-Independent Activation of p38α Mediated by TAB1-Dependent Autophosphorylation of p38α , 2002, Science.

[99]  B. Williams,et al.  p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons , 1999, The EMBO journal.

[100]  M. Gaestel,et al.  Abnormal Migration Phenotype of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2−/− Neutrophils in Zigmond Chambers Containing Formyl-Methionyl-Leucyl-Phenylalanine Gradients1 , 2001, The Journal of Immunology.

[101]  Michael E. Greenberg,et al.  Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis , 1995, Science.

[102]  C. Marshall,et al.  Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2 , 1998, Current Biology.

[103]  E. Nishida,et al.  A conserved docking motif in MAP kinases common to substrates, activators and regulators , 2000, Nature Cell Biology.

[104]  R. Janknecht.  Cell Type-specific Inhibition of the ETS Transcription Factor ER81 by Mitogen-activated Protein Kinase-activated Protein Kinase 2* , 2001, The Journal of Biological Chemistry.

[105]  O. Werz,et al.  5-lipoxygenase is phosphorylated by p38 kinase-dependent MAPKAP kinases. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[106]  J. Mudgett,et al.  Essential role for p38alpha mitogen-activated protein kinase in placental angiogenesis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[107]  A. Gingras,et al.  Human eukaryotic translation initiation factor 4G (eIF4G) recruits Mnk1 to phosphorylate eIF4E , 1999, The EMBO journal.

[108]  E. A. O'neill,et al.  Molecular basis for p38 protein kinase inhibitor specificity. , 1998, Biochemistry.

[109]  T. Yue,et al.  TL1, a Novel Tumor Necrosis Factor-like Cytokine, Induces Apoptosis in Endothelial Cells , 1999, The Journal of Biological Chemistry.

[110]  Jiahuai Han,et al.  Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation , 1997, Nature.

[111]  J. Jongstra,et al.  LSP1 Is the Major Substrate for Mitogen-activated Protein Kinase-activated Protein Kinase 2 in Human Neutrophils* , 1997, The Journal of Biological Chemistry.

[112]  Gary Brewer,et al.  Regulation of Cyclooxygenase 2 mRNA Stability by the Mitogen-Activated Protein Kinase p38 Signaling Cascade , 2000, Molecular and Cellular Biology.

[113]  W. Fiers,et al.  Tumor Necrosis Factor-induced Microtubule Stabilization Mediated by Hyperphosphorylated Oncoprotein 18 Promotes Cell Death* , 2000, The Journal of Biological Chemistry.

[114]  Melanie Allen,et al.  Deficiency of the Stress Kinase P38α Results in Embryonic Lethality , 2000, The Journal of Experimental Medicine.

[115]  J. Ju,et al.  ERK-1/2 and p38 Kinase Oppositely Regulate Nitric Oxide-induced Apoptosis of Chondrocytes in Association with p53, Caspase-3, and Differentiation Status* , 2002, The Journal of Biological Chemistry.

[116]  M. Gaestel,et al.  MAPKAP kinase 2 is activated by heat shock and TNF‐α: In vivo phosphorylation of small heat shock protein results from stimulation of the MAP kinase cascade , 1995, Journal of cellular biochemistry.

[117]  G. Kollias,et al.  Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. , 1999, Immunity.

[118]  N. Nath,et al.  Regulation of Rb and E2F by signal transduction cascades: divergent effects of JNK1 and p38 kinases , 1999, The EMBO journal.

[119]  T. Kohno,et al.  Identification of stathmin as a novel substrate for p38 delta. , 1998, Biochemical and biophysical research communications.

[120]  C. Kuo,et al.  Fas activation of the p38 mitogen-activated protein kinase signalling pathway requires ICE/CED-3 family proteases , 1997, Molecular and cellular biology.

[121]  Liang Tong,et al.  Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site , 2002 .

[122]  Jiahuai Han,et al.  The primary structure of p38 gamma: a new member of p38 group of MAP kinases. , 1996, Biochemical and biophysical research communications.

[123]  M. J. Barratt,et al.  The nucleosomal response associated with immediate‐early gene induction is mediated via alternative MAP kinase cascades: MSK1 as a potential histone H3/HMG‐14 kinase , 1999, The EMBO journal.

[124]  C. Huang,et al.  The primary structure of a human MAP kinase activated protein kinase 2. , 1994, Biochemical and biophysical research communications.

[125]  A. Fornace,et al.  p38 and Chk1 kinases: different conductors for the G(2)/M checkpoint symphony. , 2002, Current opinion in genetics & development.

[126]  Philip R. Cohen,et al.  MSK1 is required for CREB phosphorylation in response to mitogens in mouse embryonic stem cells , 2000, FEBS letters.

[127]  J C Lee,et al.  Novel homologues of CSBP/p38 MAP kinase: activation, substrate specificity and sensitivity to inhibition by pyridinyl imidazoles. , 1997, Biochemical and biophysical research communications.

[128]  Zhenguo Wu,et al.  p38 and Extracellular Signal-Regulated Kinases Regulate the Myogenic Program at Multiple Steps , 2000, Molecular and Cellular Biology.

[129]  J. Moss,et al.  Mitogen-activated Protein Kinases Mediate Activator Protein-1-dependent Human Inducible Nitric-oxide Synthase Promoter Activation* , 2001, The Journal of Biological Chemistry.

[130]  Juan Miguel Redondo,et al.  A Role for the p38 MAP Kinase Pathway in the Nuclear Shuttling of NFATp* , 2000, The Journal of Biological Chemistry.

[131]  E. Krebs,et al.  Involvement of stress-activated protein kinase and p38 mitogen-activated protein kinase in mIgM-induced apoptosis of human B lymphocytes. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[132]  M. J. Fisher,et al.  p38 Mitogen-activated Protein Kinase Phosphorylates Cytosolic Phospholipase A2 (cPLA2) in Thrombin-stimulated Platelets , 1996, The Journal of Biological Chemistry.

[133]  M. Karin,et al.  Requirement for p38α in Erythropoietin Expression A Role for Stress Kinases in Erythropoiesis , 2000, Cell.

[134]  T. Hartung,et al.  Mitogen-Activated Protein Kinase-Activated Protein Kinase 2-Deficient Mice Show Increased Susceptibility to Listeria monocytogenes Infection , 2002, The Journal of Immunology.

[135]  M. Gaestel,et al.  FRET‐based detection of different conformations of MK2 , 2001, EMBO reports.

[136]  M. Gaestel,et al.  Constitutive Activation of Mitogen-activated Protein Kinase-activated Protein Kinase 2 by Mutation of Phosphorylation Sites and an A-helix Motif (*) , 1995, The Journal of Biological Chemistry.

[137]  Michel Morange,et al.  A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins , 1994, Cell.

[138]  N. Watanabe,et al.  Exip, a new alternative splicing variant of p38 alpha, can induce an earlier onset of apoptosis in HeLa cells. , 2002, Biochemical and biophysical research communications.

[139]  J. Hsuan,et al.  Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of hsp27 , 1994, Cell.

[140]  Philip R. Cohen,et al.  Activation of stress‐activated protein kinase‐3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38) , 1997, The EMBO journal.

[141]  Michael C. Ostrowski,et al.  Microphthalmia Transcription Factor Is a Target of the p38 MAPK Pathway in Response to Receptor Activator of NF-κB Ligand Signaling* , 2002, The Journal of Biological Chemistry.

[142]  Weiya Ma,et al.  Phosphorylation of 4E-BP1 Is Mediated by the p38/MSK1 Pathway in Response to UVB Irradiation* , 2002, The Journal of Biological Chemistry.

[143]  K. Valerie,et al.  Involvement of p38 in apoptosis-associated membrane blebbing and nuclear condensation. , 2001, Molecular biology of the cell.

[144]  S. Lipton,et al.  Antiapoptotic role of the p38 mitogen-activated protein kinase-myocyte enhancer factor 2 transcription factor pathway during neuronal differentiation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[145]  A. Sharrocks,et al.  Selective Targeting of MAPKs to the ETS Domain Transcription Factor SAP-1* , 2001, The Journal of Biological Chemistry.

[146]  Jiahuai Han,et al.  Pro-inflammatory Cytokines and Environmental Stress Cause p38 Mitogen-activated Protein Kinase Activation by Dual Phosphorylation on Tyrosine and Threonine (*) , 1995, The Journal of Biological Chemistry.

[147]  K. Sakaguchi,et al.  Phosphorylation of human p53 by p38 kinase coordinates N‐terminal phosphorylation and apoptosis in response to UV radiation , 1999, The EMBO journal.

[148]  E. Nishida,et al.  Identification of a docking groove on ERK and p38 MAP kinases that regulates the specificity of docking interactions , 2001, The EMBO journal.

[149]  S. Kassis,et al.  p38 mitogen-activated protein kinase inhibitors--mechanisms and therapeutic potentials. , 1999, Pharmacology & therapeutics.

[150]  R. Kramer,et al.  Identification and Characterization of the Cell Type-specific and Developmentally Regulated α7 Integrin Gene Promoter* , 1996, The Journal of Biological Chemistry.

[151]  R. Kraft,et al.  MAPKAP Kinase 2 Phosphorylates Serum Response Factor in Vitro and in Vivo* , 1999, The Journal of Biological Chemistry.

[152]  B. Allen,et al.  Two distinct forms of MAPKAP kinase-2 in adult cardiac ventricular myocytes. , 2000, Biochemistry.

[153]  Philip R. Cohen,et al.  Identification of novel phosphorylation sites required for activation of MAPKAP kinase‐2. , 1995, The EMBO journal.

[154]  G. D. De Zutter,et al.  Pro-apoptotic gene expression mediated by the p38 mitogen-activated protein kinase signal transduction pathway , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[155]  J. Dean,et al.  A p38 MAP kinase inhibitor regulates stability of interleukin‐1‐induced cyclooxygenase‐2 mRNA , 1998, FEBS letters.

[156]  K. Miyazawa,et al.  Regulation of Interleukin-1β-induced Interleukin-6 Gene Expression in Human Fibroblast-like Synoviocytes by p38 Mitogen-activated Protein Kinase* , 1998, The Journal of Biological Chemistry.

[157]  K. Heidenreich,et al.  Apoptosis Induced by Withdrawal of Trophic Factors Is Mediated by p38 Mitogen-activated Protein Kinase* , 1997, The Journal of Biological Chemistry.

[158]  P. Cohen,et al.  The search for physiological substrates of MAP and SAP kinases in mammalian cells. , 1997, Trends in cell biology.

[159]  J. Saklatvala,et al.  Dexamethasone Destabilizes Cyclooxygenase 2 mRNA by Inhibiting Mitogen-Activated Protein Kinase p38 , 2001, Molecular and Cellular Biology.

[160]  M. Gaestel,et al.  Stress-induced Stimulation of Early Growth Response Gene-1 by p38/Stress-activated Protein Kinase 2 Is Mediated by a cAMP-responsive Promoter Element in a MAPKAP Kinase 2-independent Manner* , 1999, The Journal of Biological Chemistry.

[161]  G. Kollias,et al.  MK2 Targets AU-rich Elements and Regulates Biosynthesis of Tumor Necrosis Factor and Interleukin-6 Independently at Different Post-transcriptional Levels* , 2002, The Journal of Biological Chemistry.

[162]  J. Engelman,et al.  Specific Inhibitors of p38 Mitogen-activated Protein Kinase Block 3T3-L1 Adipogenesis* , 1998, The Journal of Biological Chemistry.

[163]  Xiaozhong Wang,et al.  Stress-Induced Phosphorylation and Activation of the Transcription Factor CHOP (GADD153) by p38 MAP Kinase , 1996, Science.

[164]  Andrew D. Sharrocks,et al.  Targeting of p38 Mitogen-Activated Protein Kinases to MEF2 Transcription Factors , 1999, Molecular and Cellular Biology.

[165]  Jonathan A. Cooper,et al.  Phosphorylation of the Cap-Binding Protein Eukaryotic Translation Initiation Factor 4E by Protein Kinase Mnk1 In Vivo , 1999, Molecular and Cellular Biology.

[166]  G. Stoecklin,et al.  Mitogen-Activated Protein Kinase Phosphatidylinositol 3-Kinase and p 38 Interleukin-3 mRNA Turnover by Parallel and Independent Regulation of , 2001 .

[167]  O. Issinger,et al.  Stress-induced Activation of Protein Kinase CK2 by Direct Interaction with p38 Mitogen-activated Protein Kinase* , 2000, The Journal of Biological Chemistry.

[168]  Jiahuai Han,et al.  Cloning and Characterization of RLPK, a Novel RSK-related Protein Kinase* , 1999, The Journal of Biological Chemistry.

[169]  J. Hedges,et al.  A role for p38(MAPK)/HSP27 pathway in smooth muscle cell migration. , 1999, The Journal of biological chemistry.

[170]  K. Browning,et al.  The Phosphorylation State of Poly(A)-binding Protein Specifies Its Binding to Poly(A) RNA and Its Interaction with Eukaryotic Initiation Factor (eIF) 4F, eIFiso4F, and eIF4B* , 2000, The Journal of Biological Chemistry.

[171]  P. Cohen,et al.  Participation of a stress-activated protein kinase cascade in the activation of tyrosine hydroxylase in chromaffin cells. , 1997, European journal of biochemistry.

[172]  Jiahuai Han,et al.  p38 Kinase is a negative regulator of angiotensin II signal transduction in vascular smooth muscle cells: effects on Na+/H+ exchange and ERK1/2. , 1998, Circulation research.

[173]  M. Karin,et al.  The stress-induced MAP kinase p38 regulates endocytic trafficking via the GDI:Rab5 complex. , 2001, Molecular cell.

[174]  X. Wang,et al.  MAPKAPK5, a novel mitogen-activated protein kinase (MAPK)-activated protein kinase, is a substrate of the extracellular-regulated kinase (ERK) and p38 kinase. , 1998, Biochemical and biophysical research communications.

[175]  E. Nishida,et al.  Activation and Involvement of p38 Mitogen-activated Protein Kinase in Glutamate-induced Apoptosis in Rat Cerebellar Granule Cells* , 1997, The Journal of Biological Chemistry.

[176]  B. Haye,et al.  Involvement of the p38 mitogen‐activated protein kinase pathway in tissue inhibitor of metalloproteinases‐1‐induced erythroid differentiation , 2000, FEBS letters.

[177]  Philip R. Cohen,et al.  Identification of anisomycin-activated kinases p45 and p55 in murine cells as MAPKAP kinase-2. , 1996, Oncogene.

[178]  P. Cohen,et al.  MSK1 and MSK2 Are Required for the Mitogen- and Stress-Induced Phosphorylation of CREB and ATF1 in Fibroblasts , 2002, Molecular and Cellular Biology.

[179]  J. Landry,et al.  Modulation of actin microfilament dynamics and fluid phase pinocytosis by phosphorylation of heat shock protein 27. , 1993, The Journal of biological chemistry.

[180]  Philip R. Cohen,et al.  The substrate specificity and structure of mitogen-activated protein (MAP) kinase-activated protein kinase-2. , 1993, The Biochemical journal.

[181]  A. Gingras,et al.  eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. , 1999, Annual review of biochemistry.

[182]  P. Cohen,et al.  Conversion of SB 203580-insensitive MAP kinase family members to drug-sensitive forms by a single amino-acid substitution. , 1998, Chemistry & biology.

[183]  S. E. D. Laszlo.  Pyrroles and Other Heterocycles as Inhibitors of P38 Kinase. , 1999 .

[184]  S. Saga,et al.  Phosphorylation of αB-crystallin in Mitotic Cells and Identification of Enzymatic Activities Responsible for Phosphorylation* , 1998, The Journal of Biological Chemistry.

[185]  Philip R. Cohen,et al.  A comparison of the substrate specificity of MAPKAP kinase‐2 and MAPKAP kinase‐3 and their activation by cytokines and cellular stress , 1996, FEBS letters.

[186]  T. Hunter,et al.  The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification 1 , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[187]  R. Kothary,et al.  MEF2 is upregulated during cardiac hypertrophy and is required for normal post-natal growth of the myocardium , 1999, Current Biology.

[188]  P. Cohen,et al.  MAPKAP kinase‐2; a novel protein kinase activated by mitogen‐activated protein kinase. , 1992, The EMBO journal.

[189]  Jiahuai Han,et al.  The p38 signal transduction pathway: activation and function. , 2000, Cellular signalling.

[190]  Jiandie D. Lin,et al.  Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1. , 2001, Molecular cell.

[191]  E. Bengal,et al.  p38 Mitogen-activated Protein Kinase Pathway Promotes Skeletal Muscle Differentiation , 1999, The Journal of Biological Chemistry.

[192]  Jerry L. Adams,et al.  A protein kinase involved in the regulation of inflammatory cytokine biosynthesis , 1994, Nature.

[193]  R. Flavell,et al.  Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for tumor necrosis factor-induced cytokine expression. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[194]  M. Houde,et al.  Intestinal Epithelial Cell Differentiation Involves Activation of p38 Mitogen-activated Protein Kinase That Regulates the Homeobox Transcription Factor CDX2* , 2001, The Journal of Biological Chemistry.

[195]  Klaus Resch,et al.  The p38 MAP kinase pathway signals for cytokine‐induced mRNA stabilization via MAP kinase‐activated protein kinase 2 and an AU‐rich region‐targeted mechanism , 1999, The EMBO journal.

[196]  D. Zechner,et al.  MKK6 Activates Myocardial Cell NF-κB and Inhibits Apoptosis in a p38 Mitogen-activated Protein Kinase-dependent Manner* , 1998, The Journal of Biological Chemistry.

[197]  J. Hedges,et al.  A Role for p38MAPK/HSP27 Pathway in Smooth Muscle Cell Migration* , 1999, The Journal of Biological Chemistry.

[198]  Elizabeth J. Goldsmith,et al.  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* , 1998, The Journal of Biological Chemistry.

[199]  D. Alessi,et al.  Mitogen‐ and stress‐activated protein kinase‐1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB , 1998, The EMBO journal.

[200]  Wei Guo,et al.  Characterization of the Structure and Function of a New Mitogen-activated Protein Kinase (p38β)* , 1996, The Journal of Biological Chemistry.