The complexity of mitogen-activated protein kinases (MAPKs) made simple

Abstract.The mitogen-activated protein kinase (MAPK) pathways are known to be involved in various processes of growth, differentiation and cell death. In spite of their ubiquitous presence and seemingly enormous cross-talk with each other, their action is very specific. This review deals with various aspects of the three different MAPK pathways (ERK, p38 and JNK) and how their specificity is brought about.

[1]  J. Pouysségur,et al.  Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling. , 2002, European journal of biochemistry.

[2]  K Kornfeld,et al.  Docking Sites on Substrate Proteins Direct Extracellular Signal-regulated Kinase to Phosphorylate Specific Residues* , 2001, The Journal of Biological Chemistry.

[3]  M. C. Hu,et al.  Murine p38-δ Mitogen-activated Protein Kinase, a Developmentally Regulated Protein Kinase That Is Activated by Stress and Proinflammatory Cytokines* , 1999, The Journal of Biological Chemistry.

[4]  A. Yoshimura,et al.  The Sprouty-related protein, Spred, inhibits cell motility, metastasis, and Rho-mediated actin reorganization , 2004, Oncogene.

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

[6]  S. Akira,et al.  TLR8-mediated NF-kappaB and JNK activation are TAK1-independent and MEKK3-dependent. , 2006, The Journal of biological chemistry.

[7]  T. Maeda,et al.  Regulation of the Saccharomyces cerevisiae HOG1 mitogen-activated protein kinase by the PTP2 and PTP3 protein tyrosine phosphatases , 1997, Molecular and cellular biology.

[8]  J. Woodgett,et al.  Mitogen-Activated Protein Kinases , 2010 .

[9]  Roger J. Davis,et al.  Selective Activation of p38 Mitogen-activated Protein (MAP) Kinase Isoforms by the MAP Kinase Kinases MKK3 and MKK6* , 1998, The Journal of Biological Chemistry.

[10]  A. Strasser,et al.  Activation of the mitogen-activated protein kinase pathway induces transcription of the PAC-1 phosphatase gene , 1996, Molecular and cellular biology.

[11]  T. Hunter,et al.  MEKK1 Mediates the Ubiquitination and Degradation of c-Jun in Response to Osmotic Stress , 2006, Molecular and Cellular Biology.

[12]  J. Blenis,et al.  mTOR, translational control and human disease. , 2005, Seminars in cell & developmental biology.

[13]  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.

[14]  Seung-Wook Ryu,et al.  JNK- and p38 Kinase-mediated Phosphorylation of Bax Leads to Its Activation and Mitochondrial Translocation and to Apoptosis of Human Hepatoma HepG2 Cells* , 2006, Journal of Biological Chemistry.

[15]  Elizabeth Yang,et al.  Serine Phosphorylation of Death Agonist BAD in Response to Survival Factor Results in Binding to 14-3-3 Not BCL-XL , 1996, Cell.

[16]  W. Lieberthal,et al.  Inhibition of Ligand-independent ERK1/2 Activity in Kidney Proximal Tubular Cells Deprived of Soluble Survival Factors Up-regulates Akt and Prevents Apoptosis* , 2004, Journal of Biological Chemistry.

[17]  N. Holbrook,et al.  Requirement for ERK Activation in Cisplatin-induced Apoptosis* , 2000, The Journal of Biological Chemistry.

[18]  J. Pouysségur,et al.  Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Eilers,et al.  Transcriptional regulation and transformation by Myc proteins , 2005, Nature Reviews Molecular Cell Biology.

[20]  E. Wagner,et al.  Liver Tumor Development c-Jun Antagonizes the Proapoptotic Activity of p53 , 2003, Cell.

[21]  N. Won,et al.  MEK inhibitor, U0126, attenuates cisplatin-induced renal injury by decreasing inflammation and apoptosis. , 2005, Kidney international.

[22]  P. Rakic,et al.  Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene , 1997, Nature.

[23]  A. Nebreda,et al.  Reactivating Kinase/p38 Phosphorylates τ Protein In Vitro , 1997 .

[24]  M. Muda,et al.  Bcl-2 Undergoes Phosphorylation by c-Jun N-terminal Kinase/Stress-activated Protein Kinases in the Presence of the Constitutively Active GTP-binding Protein Rac1* , 1997, The Journal of Biological Chemistry.

[25]  E. Wimmer,et al.  MAP Kinase Phosphatase As a Locus of Flexibility in a Mitogen-Activated Protein Kinase Signaling Network , 2022 .

[26]  A. Ashworth,et al.  The Dual Specificity Phosphatases M3/6 and MKP-3 Are Highly Selective for Inactivation of Distinct Mitogen-activated Protein Kinases* , 1996, The Journal of Biological Chemistry.

[27]  Li‐jun Wu,et al.  Phosphorylated extracellular signal-regulated kinase up-regulated p53 expression in shikonin-induced HeLa cell apoptosis. , 2005, Chinese medical journal.

[28]  V. Fried,et al.  c-Jun NH2-terminal Kinases Target the Ubiquitination of Their Associated Transcription Factors* , 1997, The Journal of Biological Chemistry.

[29]  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.

[30]  Z. Goldsmith,et al.  G Protein regulation of MAPK networks , 2007, Oncogene.

[31]  S. Keyse,et al.  Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. , 2000, Current opinion in cell biology.

[32]  Ping Huang,et al.  Activation of extracellular signal-regulated kinase mediates apoptosis induced by uropathogenic Escherichia coli toxins via nitric oxide synthase: protective role of heme oxygenase-1. , 2004, The Journal of infectious diseases.

[33]  S. R. Datta,et al.  Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. , 1999, Science.

[34]  J. Kornhauser,et al.  Nerve Growth Factor Activates Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Pathways To Stimulate CREB Serine 133 Phosphorylation , 1998, Molecular and Cellular Biology.

[35]  M. Kaplan,et al.  The p38 mitogen-activated protein kinase is required for IL-12-induced IFN-gamma expression. , 2000, Journal of immunology.

[36]  T. Monks,et al.  Histone H3 phosphorylation is coupled to poly-(ADP-ribosylation) during reactive oxygen species-induced cell death in renal proximal tubular epithelial cells. , 2001, Molecular pharmacology.

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

[38]  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.

[39]  H. Grunicke,et al.  Novel Membrane-Targeted ERK1 and ERK2 Chimeras Which Act as Dominant Negative, Isotype-Specific Mitogen-Activated Protein Kinase Inhibitors of Ras-Raf-Mediated Transcriptional Activation of c-fos in NIH 3T3 Cells , 1999, Molecular and Cellular Biology.

[40]  Hong Sun,et al.  MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo , 1993, Cell.

[41]  K. Yoshioka,et al.  A Novel Mechanism of JNK1 Activation , 1997, The Journal of Biological Chemistry.

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

[43]  Kunio Kondoh,et al.  The duration, magnitude and compartmentalization of ERK MAP kinase activity: mechanisms for providing signaling specificity , 2005, Journal of Cell Science.

[44]  T. Blom,et al.  Sphingosine kinase as an oncogene: autocrine sphingosine 1-phosphate modulates ML-1 thyroid carcinoma cell migration by a mechanism dependent on protein kinase C-alpha and ERK1/2. , 2009, Endocrinology.

[45]  H. Schaeffer,et al.  MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. , 1998, Science.

[46]  M. Miura,et al.  Regulatory roles of JNK in programmed cell death. , 2004, Journal of biochemistry.

[47]  Fuminori Tsuruta,et al.  JNK antagonizes Akt-mediated survival signals by phosphorylating 14-3-3 , 2005, The Journal of cell biology.

[48]  B. Cuevas,et al.  Wiring diagrams of MAPK regulation by MEKK1, 2, and 3. , 2004, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[49]  Veeranna,et al.  Phosphorylation of MEK1 by cdk5/p35 Down-regulates the Mitogen-activated Protein Kinase Pathway* , 2002, The Journal of Biological Chemistry.

[50]  Dirk Bohmann,et al.  Reduced Ubiquitin-Dependent Degradation of c-Jun After Phosphorylation by MAP Kinases , 1997, Science.

[51]  Philip R. Cohen,et al.  FGF and stress regulate CREB and ATF‐1 via a pathway involving p38 MAP kinase and MAPKAP kinase‐2. , 1996, The EMBO journal.

[52]  J. Downward.  Targeting RAS signalling pathways in cancer therapy , 2003, Nature Reviews Cancer.

[53]  A. Nebreda,et al.  Reactivating kinase/p38 phosphorylates tau protein in vitro. , 1997, Journal of neurochemistry.

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

[55]  D. Beach,et al.  Cdc25 cell-cycle phosphatase as a target of c-myc , 1996, Nature.

[56]  Jingliu,et al.  Role of JNK activation in apoptosis： A double-edged sword , 2005 .

[57]  R. Park,et al.  Nitric oxide inhibits c-Jun N-terminal kinase 2 (JNK2) via S-nitrosylation. , 1998, Biochemical and biophysical research communications.

[58]  E. Wagner,et al.  Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation , 2000, Oncogene.

[59]  H. K. Sluss,et al.  Selective interaction of JNK protein kinase isoforms with transcription factors. , 1996, The EMBO journal.

[60]  R. Davis,et al.  Regulation of MAP kinases by docking domains , 2001, Biology of the cell.

[61]  J. Blenis,et al.  MAPK signal specificity: the right place at the right time. , 2006, Trends in biochemical sciences.

[62]  S. Kostka,et al.  Affinity purification of ARE-binding proteins identifies polyA-binding protein 1 as a potential substrate in MK2-induced mRNA stabilization. , 2003, Biochemical and biophysical research communications.

[63]  Y. Kohno,et al.  The KDEL Receptor Modulates the Endoplasmic Reticulum Stress Response through Mitogen-activated Protein Kinase Signaling Cascades* , 2003, Journal of Biological Chemistry.

[64]  E. Goldsmith,et al.  A constitutively active and nuclear form of the MAP kinase ERK2 is sufficient for neurite outgrowth and cell transformation , 1998, Current Biology.

[65]  M. Chaussepied,et al.  Upregulation of Jun and Fos family members and permanent JNK activity lead to constitutive AP-1 activation in Theileria-transformed leukocytes. , 1998, Molecular and biochemical parasitology.

[66]  P. Neufer,et al.  Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity. , 2006, Cell metabolism.

[67]  M. Krishna,et al.  Effect of nitric oxide donor and gamma irradiation on MAPK signaling in murine peritoneal macrophages , 2008, Journal of cellular biochemistry.

[68]  Stella Pelengaris,et al.  c-MYC: more than just a matter of life and death , 2002, Nature Reviews Cancer.

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

[70]  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.

[71]  Prahlad T. Ram,et al.  MAP Kinase Phosphatase As a Locus of Flexibility in a Mitogen-Activated Protein Kinase Signaling Network , 2002, Science.

[72]  J. Avruch,et al.  Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. , 2001, Physiological reviews.

[73]  K. Reddy,et al.  Role of MAP kinase in tumor progression and invasion , 2003, Cancer and Metastasis Reviews.

[74]  Francesc Posas,et al.  Yeast HOG1 MAP Kinase Cascade Is Regulated by a Multistep Phosphorelay Mechanism in the SLN1–YPD1–SSK1 “Two-Component” Osmosensor , 1996, Cell.

[75]  G. Nowak.  Protein Kinase C- (cid:1) and ERK1/2 Mediate Mitochondrial Dysfunction, Decreases in Active Na (cid:2) Transport, and Cisplatin-induced Apoptosis in Renal Cells* , 2022 .

[76]  R. Flavell,et al.  JNK is required for effector T-cell function but not for T-cell activation , 2000, Nature.

[77]  Michael Karin,et al.  A central role for JNK in obesity and insulin resistance , 2002, Nature.

[78]  Kazuhito Yamamoto,et al.  BCL-2 Is Phosphorylated and Inactivated by an ASK1/Jun N-Terminal Protein Kinase Pathway Normally Activated at G2/M , 1999, Molecular and Cellular Biology.

[79]  C. An,et al.  Leptin Induces Apoptosis via ERK/cPLA2/Cytochrome c Pathway in Human Bone Marrow Stromal Cells* , 2003, Journal of Biological Chemistry.

[80]  O. Bachar,et al.  Toll‐like receptor stimulation induces airway hyper‐responsiveness to bradykinin, an effect mediated by JNK and NF‐κB signaling pathways , 2004 .

[81]  S. Rosenfeld,et al.  Lysophosphatidic acid stimulates actomyosin contraction in astrocytes , 1998, Journal of neuroscience research.

[82]  Y. Kohda,et al.  Involvement of activation of NADPH oxidase and extracellular signal-regulated kinase (ERK) in renal cell injury induced by zinc. , 2005, The Journal of toxicological sciences.

[83]  M. Karin,et al.  Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73 , 1991, Nature.

[84]  A. Ullrich,et al.  PTP‐SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal‐regulated kinases ERK1 and ERK2 by association through a kinase interaction motif , 1998, The EMBO journal.

[85]  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.

[86]  R. Flavell,et al.  Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5 , 2004, Nature.

[87]  辻田 英司.  Suppressed MKP-1 is an independent predictor of outcome in patients with hepatocellular carcinoma , 2006 .

[88]  N. Osheroff,et al.  Extracellular Signal-Regulated Kinase Activates Topoisomerase IIα through a Mechanism Independent of Phosphorylation , 1999, Molecular and Cellular Biology.

[89]  C. Marshall,et al.  Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation , 1995, Cell.

[90]  H. Monteiro.  Signal transduction by protein tyrosine nitration: competition or cooperation with tyrosine phosphorylation-dependent signaling events? , 2002, Free radical biology & medicine.

[91]  N. Kennedy,et al.  Role of JNK in Tumor Development , 2003, Cell cycle.

[92]  G. Salvesen,et al.  The Regulation of Anoikis: MEKK-1 Activation Requires Cleavage by Caspases , 1997, Cell.

[93]  E. Feldman,et al.  Bidirectional Regulation of p38 Kinase and c-Jun N-terminal Protein Kinase by Insulin-like Growth Factor-I* , 1998, The Journal of Biological Chemistry.

[94]  J. Olson,et al.  p38 MAP kinase: a convergence point in cancer therapy. , 2004, Trends in molecular medicine.

[95]  C. Moskaluk,et al.  PAC-1: a mitogen-induced nuclear protein tyrosine phosphatase. , 1993, Science.

[96]  Jeonghee Cho,et al.  Tpl2/Cot Signals Activate ERK, JNK, and NF-κB in a Cell-type and Stimulus-specific Manner* , 2005, Journal of Biological Chemistry.

[97]  M. Bogoyevitch,et al.  The c-Jun N-terminal protein kinase family of mitogen-activated protein kinases (JNK MAPKs). , 2001, The international journal of biochemistry & cell biology.

[98]  M. Gabrielsen,et al.  Distinct Binding Determinants for ERK2/p38α and JNK MAP Kinases Mediate Catalytic Activation and Substrate Selectivity of MAP Kinase Phosphatase-1* 210 , 2001, The Journal of Biological Chemistry.

[99]  A. Ashworth,et al.  MAP kinase phosphatases , 2002, Genome Biology.

[100]  S. Korsmeyer,et al.  Bad, a heterodimeric partner for Bcl-xL and Bcl-2, displaces bax and promotes cell death , 1995, Cell.

[101]  S. Y. Cajal,et al.  Role of the p38 MAPK pathway in cisplatin-based therapy , 2003, Oncogene.

[102]  C. Dani,et al.  Retinoic acid activation of the ERK pathway is required for embryonic stem cell commitment into the adipocyte lineage. , 2002, The Biochemical journal.

[103]  J. Blenis,et al.  Characterization of Regulatory Events Associated with Membrane Targeting of p90 Ribosomal S6 Kinase 1 , 2001, Molecular and Cellular Biology.

[104]  J. Avruch,et al.  pp54 microtubule-associated protein 2 kinase. A novel serine/threonine protein kinase regulated by phosphorylation and stimulated by poly-L-lysine. , 1990, The Journal of biological chemistry.

[105]  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.

[106]  E. Sahai,et al.  Cross‐talk between Ras and Rho signalling pathways in transformation favours proliferation and increased motility , 2001, The EMBO journal.

[107]  P. Ping,et al.  Nitric oxide (NO) induces nitration of protein kinase Cepsilon (PKCepsilon ), facilitating PKCepsilon translocation via enhanced PKCepsilon -RACK2 interactions: a novel mechanism of no-triggered activation of PKCepsilon. , 2002, The Journal of biological chemistry.

[108]  M. Roussel,et al.  Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1). , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[109]  G. Fanger,et al.  Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption. , 1998, Science.

[110]  E. Nishida,et al.  Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway , 2002, Nature Cell Biology.

[111]  H. Schulze-Koops,et al.  The p38 mitogen-activated protein kinase signaling cascade in CD4 T cells , 2006, Arthritis research & therapy.

[112]  J. Thompson,et al.  Tyrosine nitration of c-SRC tyrosine kinase in human pancreatic ductal adenocarcinoma. , 2000, Archives of biochemistry and biophysics.

[113]  W. Kolch.  Coordinating ERK/MAPK signalling through scaffolds and inhibitors , 2005, Nature Reviews Molecular Cell Biology.

[114]  D. Green,et al.  The c-Jun N-terminal kinase cascade plays a role in stress-induced apoptosis in Jurkat cells by up-regulating Fas ligand expression. , 1998, Journal of immunology.

[115]  G. Nemerow,et al.  MEK kinase 1 is critically required for c-Jun N-terminal kinase activation by proinflammatory stimuli and growth factor-induced cell migration. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[116]  Weiya Ma,et al.  Activation of JNK1, RSK2, and MSK1 Is Involved in Serine 112 Phosphorylation of Bad by Ultraviolet B Radiation* , 2002, The Journal of Biological Chemistry.

[117]  Bostjan Kobe,et al.  Uses for JNK: the Many and Varied Substrates of the c-Jun N-Terminal Kinases , 2006, Microbiology and Molecular Biology Reviews.

[118]  S. Meloche,et al.  Inhibition of Growth Factor-induced Protein Synthesis by a Selective MEK Inhibitor in Aortic Smooth Muscle Cells* , 1996, The Journal of Biological Chemistry.

[119]  N. Sonenberg,et al.  Translation initiation of ornithine decarboxylase and nucleocytoplasmic transport of cyclin D1 mRNA are increased in cells overexpressing eukaryotic initiation factor 4E. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[120]  M. McDevitt,et al.  The HBP1 transcriptional repressor and the p38 MAP kinase: unlikely partners in G1 regulation and tumor suppression. , 2004, Gene.

[121]  J. Blenis,et al.  ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK , 1992, Cell.

[122]  S. Lai,et al.  Induced eosinophilia and proliferation in Angiostrongylus cantonensis-infected mouse brain are associated with the induction of JAK/STAT1, IAP/NF-kappaB and MEKK1/JNK signals. , 2004, Journal of helminthology.

[123]  N. Ahn,et al.  Signal transduction through MAP kinase cascades. , 1998, Advances in cancer research.

[124]  P. Cohen,et al.  Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines , 1995, Current Biology.

[125]  L. Mahadevan,et al.  MAP kinase-mediated signalling to nucleosomes and immediate-early gene induction. , 1999, Seminars in cell & developmental biology.

[126]  P. Ping,et al.  Nitric Oxide (NO) Induces Nitration of Protein Kinase Cε (PKCε), Facilitating PKCε Translocation via Enhanced PKCε-RACK2 Interactions , 2002, The Journal of Biological Chemistry.

[127]  S. Akira,et al.  TLR8-mediated NF-κB and JNK Activation Are TAK1-independent and MEKK3-dependent* , 2006, Journal of Biological Chemistry.

[128]  E. Lander,et al.  Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[129]  S. Akira,et al.  Essential function for the kinase TAK1 in innate and adaptive immune responses , 2005, Nature Immunology.

[130]  B. Dérijard,et al.  Cdc42 and PAK-mediated Signaling Leads to Jun Kinase and p38 Mitogen-activated Protein Kinase Activation (*) , 1995, The Journal of Biological Chemistry.

[131]  N. Hayashi,et al.  Involvement of the p38 mitogen‐activated protein kinase cascade in hepatocellular carcinoma , 2003, Cancer.

[132]  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 .

[133]  Yong-Yeon Cho,et al.  Cell apoptosis: requirement of H2AX in DNA ladder formation, but not for the activation of caspase-3. , 2006, Molecular cell.

[134]  Akiko Shimamura,et al.  Ribosomal S6 kinase 1 (RSK1) activation requires signals dependent on and independent of the MAP kinase ERK , 1999, Current Biology.

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

[136]  M. Muda,et al.  The Mitogen-activated Protein Kinase Phosphatase-3 N-terminal Noncatalytic Region Is Responsible for Tight Substrate Binding and Enzymatic Specificity* , 1998, The Journal of Biological Chemistry.

[137]  C. Allis,et al.  Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3. , 1999, Science.

[138]  Jiahuai Han,et al.  Activation and signaling of the p38 MAP kinase pathway , 2005, Cell Research.

[139]  Chao Zhang,et al.  Chemical genetic analysis of the time course of signal transduction by JNK. , 2006, Molecular cell.

[140]  P. Russell,et al.  Cell-cycle control linked to extracellular environment by MAP kinase pathway in fission yeast , 1995, Nature.

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

[142]  E. Wagner,et al.  Control of cell cycle progression by c-Jun is p53 dependent. , 1999, Genes & development.

[143]  E. Nishida,et al.  Molecular recognitions in the MAP kinase cascades. , 2003, Cellular signalling.

[144]  Y. Kaziro,et al.  Activation of p38 Mitogen-activated Protein Kinase by Signaling through G Protein-coupled Receptors , 1997, The Journal of Biological Chemistry.

[145]  Weiya Ma,et al.  UVA Induces Ser381 Phosphorylation of p90RSK/MAPKAP-K1 via ERK and JNK Pathways* , 2001, The Journal of Biological Chemistry.

[146]  E. Wagner,et al.  AP-1: a double-edged sword in tumorigenesis , 2003, Nature Reviews Cancer.

[147]  E. Wagner,et al.  Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation , 1999, Nature Genetics.

[148]  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.

[149]  V. Adler,et al.  JNK targets p53 ubiquitination and degradation in nonstressed cells. , 1998, Genes & development.

[150]  A. Israël,et al.  IκBα is a target for the mitogen‐activated 90 kDa ribosomal S6 kinase , 1997 .

[151]  M. Camps,et al.  Dual specificity phosphatases: a gene family for control of MAP kinase function , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[152]  Y. J. Kang,et al.  The role of the p38 pathway in adaptive immunity. , 2007, Cellular & molecular immunology.

[153]  Kenneth M. Murphy,et al.  Kinase Suppressor of Ras (KSR) Is a Scaffold Which Facilitates Mitogen-Activated Protein Kinase Activation In Vivo , 2002, Molecular and Cellular Biology.

[154]  D. Morrison,et al.  Regulation of MAP kinase signaling modules by scaffold proteins in mammals. , 2003, Annual review of cell and developmental biology.

[155]  P. Sathyanarayana,et al.  Cross-talk between JNK/SAPK and ERK/MAPK Pathways , 2003, Journal of Biological Chemistry.

[156]  S. Meloche,et al.  An essential function of the mitogen‐activated protein kinase Erk2 in mouse trophoblast development , 2003, EMBO reports.

[157]  Michael E. Greenberg,et al.  Coupling of the RAS-MAPK Pathway to Gene Activation by RSK2, a Growth Factor-Regulated CREB Kinase , 1996, Science.

[158]  N. Bhat,et al.  Hydrogen Peroxide Activation of Multiple Mitogen‐Activated Protein Kinases in an Oligodendrocyte Cell Line , 1999, Journal of neurochemistry.

[159]  R. Buchsbaum,et al.  Interaction of Rac Exchange Factors Tiam1 and Ras-GRF1 with a Scaffold for the p38 Mitogen-Activated Protein Kinase Cascade , 2002, Molecular and Cellular Biology.

[160]  L. Mahadevan,et al.  MAP kinase‐mediated phosphoacetylation of histone H3 and inducible gene regulation , 2003, FEBS letters.

[161]  L. Staszewski,et al.  Ubiquitin-dependent c-Jun degradation in vivo is mediated by the δ domain , 1994, Cell.

[162]  E. Nishida,et al.  A Novel MAPK phosphatase MKP-7 acts preferentially on JNK/SAPK and p38 alpha and beta MAPKs. , 2001, The Journal of biological chemistry.

[163]  A. Gavin,et al.  A link between MAP kinase and p34cdc2/cyclin B during oocyte maturation: p90rsk phosphorylates and inactivates the p34cdc2 inhibitory kinase Myt1 , 1998, The EMBO journal.

[164]  Dirk Bohmann,et al.  Diverse functions of JNK signaling and c-Jun in stress response and apoptosis , 1999, Oncogene.

[165]  M. Karin,et al.  The E3 Ubiquitin Ligase Itch Couples JNK Activation to TNFα-induced Cell Death by Inducing c-FLIPL Turnover , 2006, Cell.

[166]  Sankar Ghosh,et al.  Signaling to NF-kappaB. , 2004, Genes & development.

[167]  John C. Lee,et al.  Hemopoietic Growth Factors with the Exception of Interleukin-4 Activate the p38 Mitogen-activated Protein Kinase Pathway* , 1997, The Journal of Biological Chemistry.

[168]  C. Bradham,et al.  p38 MAPK in Development and Cancer , 2006, Cell cycle.

[169]  D. Eizirik,et al.  Activation of extracellular signal-regulated kinase (ERK)1/2 contributes to cytokine-induced apoptosis in purified rat pancreatic beta-cells. , 2000, European cytokine network.

[170]  J. Swantek,et al.  New insights into the control of MAP kinase pathways. , 1999, Experimental Cell Research.

[171]  F. Iborra,et al.  MAP kinase-mediated phosphorylation of distinct pools of histone H3 at S10 or S28 via mitogen- and stress-activated kinase 1/2 , 2005, Journal of Cell Science.

[172]  H. Rubinfeld,et al.  The ERK cascade as a prototype of MAPK signaling pathways. , 2004, Methods in molecular biology.

[173]  R. Seger,et al.  The extracellular signal-regulated kinase: Multiple substrates regulate diverse cellular functions , 2006, Growth factors.

[174]  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.

[175]  D. Morrison,et al.  Integrating signals from RTKs to ERK/MAPK , 2007, Oncogene.

[176]  R. Flavell,et al.  Defective T cell differentiation in the absence of Jnk1. , 1998, Science.

[177]  H. Suh,et al.  Lysophosphatidic acid stimulates CREB through mitogen- and stress-activated protein kinase-1. , 2003, Biochemical and biophysical research communications.

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

[179]  A. Nordheim,et al.  The kinase MSK1 is required for induction of c-fos by lysophosphatidic acid in mouse embryonic stem cells , 2003, BMC Molecular Biology.

[180]  T. Hunter,et al.  C/EBPbeta phosphorylation by RSK creates a functional XEXD caspase inhibitory box critical for cell survival. , 2001, Molecular cell.

[181]  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.

[182]  L. Martin,et al.  Immature and Mature Cortical Neurons Engage Different Apoptotic Mechanisms Involving Caspase-3 and the Mitogen-Activated Protein Kinase Pathway , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[183]  M. Karin,et al.  Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[184]  K Kornfeld,et al.  Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase. , 1999, Genes & development.

[185]  W. Ansorge,et al.  Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27 , 1999, The EMBO journal.

[186]  S. Benchimol,et al.  The Involvement of MAPK Signaling Pathways in Determining the Cellular Response to p53 Activation , 2006, Journal of Biological Chemistry.

[187]  R. Seger,et al.  Protein-protein interactions in the regulation of the extracellular signal-regulated kinase , 2005, Molecular biotechnology.

[188]  A Sewing,et al.  High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1 , 1997, Molecular and cellular biology.

[189]  Jiahuai Han,et al.  Rho Family GTPases Regulate p38 Mitogen-activated Protein Kinase through the Downstream Mediator Pak1 (*) , 1995, The Journal of Biological Chemistry.

[190]  Z. Ronai,et al.  Phosphorylation-dependent targeting of c-Jun ubiquitination by Jun N-kinase. , 1996, Oncogene.

[191]  C. Widmann,et al.  MEK Kinase 1, a Substrate for DEVD-Directed Caspases, Is Involved in Genotoxin-Induced Apoptosis , 1998, Molecular and Cellular Biology.

[192]  Mutsuhiro Takekawa,et al.  Protein phosphatase 2Cα inhibits the human stress‐responsive p38 and JNK MAPK pathways , 1998, The EMBO journal.

[193]  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.

[194]  Chen Dong,et al.  MAP kinases in the immune response. , 2002, Annual review of immunology.

[195]  A. Hanauer,et al.  Coffin-Lowry syndrome: current status. , 1999, American journal of medical genetics.

[196]  R. Lefkowitz,et al.  New mechanisms in heptahelical receptor signaling to mitogen activated protein kinase cascades , 2001, Oncogene.

[197]  P. Cohen,et al.  EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor , 1994, Current Biology.

[198]  G. Cooper,et al.  B-Raf Inhibits Programmed Cell Death Downstream of Cytochrome c Release from Mitochondria by Activating the MEK/Erk Pathway , 1999, Molecular and Cellular Biology.

[199]  J. Weisel,et al.  Pro-thrombotic State Induced by Post-translational Modification of Fibrinogen by Reactive Nitrogen Species* , 2004, Journal of Biological Chemistry.

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

[201]  S. So,et al.  Sprouty 2, an inhibitor of mitogen-activated protein kinase signaling, is down-regulated in hepatocellular carcinoma. , 2006, Cancer research.

[202]  M. Cobb,et al.  MAP Kinase Modules: Many Roads Home , 2003, Current Biology.

[203]  John J. Andreucci,et al.  Regulation of vertebrate myotome development by the p38 MAP kinase-MEF2 signaling pathway. , 2005, Developmental biology.

[204]  F. Posas,et al.  A human homolog of the yeast Ssk2/Ssk22 MAP kinase kinase kinases, MTK1, mediates stress‐induced activation of the p38 and JNK pathways , 1997, The EMBO journal.

[205]  Roger J. Davis,et al.  cPLA2 is phosphorylated and activated by MAP kinase , 1993, Cell.

[206]  R. Davis,et al.  Signal Transduction by the JNK Group of MAP Kinases , 2000, Cell.

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

[208]  Hui-Taek Kim,et al.  Role of mitogen-activated protein kinases in hydrogen peroxide-induced cell death in osteoblastic cells. , 2005, Toxicology.

[209]  Shinya Kuroda,et al.  Prediction and validation of the distinct dynamics of transient and sustained ERK activation , 2005, Nature Cell Biology.

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

[211]  T. Hunter,et al.  Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation , 2002, Nature Immunology.

[212]  Z. Ronai,et al.  Ubiquitin Chains in the Ladder of MAPK Signaling , 2005, Science's STKE.

[213]  K. Murayama,et al.  Reduction of insulin-stimulated glucose uptake by peroxynitrite is concurrent with tyrosine nitration of insulin receptor substrate-1. , 2004, Biochemical and biophysical research communications.

[214]  T. Hunter,et al.  The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. , 2002, Molecular cell.

[215]  J. Blenis,et al.  Nuclear localization and regulation of erk- and rsk-encoded protein kinases , 1992, Molecular and cellular biology.

[216]  Michael D. Schneider,et al.  The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function , 2006, Nature Immunology.

[217]  James M. Roberts,et al.  Cooperative Regulation of the Cell Division Cycle by the Protein Kinases RAF and AKT , 2004, Molecular and Cellular Biology.

[218]  D. Alessi,et al.  Differential regulation of the MAP, SAP and RK/p38 kinases by Pyst1, a novel cytosolic dual‐specificity phosphatase. , 1996, The EMBO journal.

[219]  Zhong Yao and Rony Seger.  The Molecular Mechanism of MAPK / ERK Inactivation , 2004 .

[220]  M. Tremblay,et al.  Mek2 Is Dispensable for Mouse Growth and Development , 2003, Molecular and Cellular Biology.

[221]  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.

[222]  J. Pouysségur,et al.  Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. , 1999, Science.

[223]  R. Flavell,et al.  Role of MLK3 in the Regulation of Mitogen-Activated Protein Kinase Signaling Cascades , 2005, Molecular and Cellular Biology.

[224]  B. Vanhaesebroeck,et al.  The PI3K-PDK1 connection: more than just a road to PKB. , 2000, The Biochemical journal.

[225]  K. Giehl.  Oncogenic Ras in tumour progression and metastasis , 2005, Biological chemistry.

[226]  A. Kolbus,et al.  ERK and Beyond: Insights from B-Raf and Raf-1 Conditional Knockouts , 2006, Cell cycle.

[227]  A. Ashworth,et al.  Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion. , 1996, Circulation research.

[228]  Ken Jacobson,et al.  MAP kinases and cell migration , 2004, Journal of Cell Science.

[229]  A. Brunet,et al.  Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts , 1993, The Journal of cell biology.

[230]  M. Karin,et al.  Jun Turnover Is Controlled Through JNK-Dependent Phosphorylation of the E3 Ligase Itch , 2004, Science.

[231]  P. Cohen,et al.  Inhibition of SAPK2a/p38 prevents hnRNP A0 phosphorylation by MAPKAP‐K2 and its interaction with cytokine mRNAs , 2002, The EMBO journal.