Mechanisms and functions of p38 MAPK signalling

Biochemical Journal - Tập 429 Số 3 - Trang 403-417 - 2010
Ana Cuadrado1, Àngel R. Nebreda1
1CNIO (Spanish National Cancer Center), Melchor Fernández Almagro 3, 28029 Madrid, Spain

Tóm tắt

The p38 MAPK (mitogen-activated protein kinase) signalling pathway allows cells to interpret a wide range of external signals and respond appropriately by generating a plethora of different biological effects. The diversity and specificity in cellular outcomes is achieved with an apparently simple linear architecture of the pathway, consisting of a core of three protein kinases acting sequentially. In the present review, we dissect the molecular mechanisms underlying p38 MAPK functions, with special emphasis on the activation and regulation of the core kinases, the interplay with other signalling pathways and the nature of p38 MAPK substrates as a source of functional diversity. Finally, we discuss how genetic mouse models are facilitating the identification of physiological functions for p38 MAPKs, which may impinge on their eventual use as therapeutic targets.

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Tài liệu tham khảo

Nebreda, 2000, p38 MAP kinases: beyond the stress response, Trends Biochem. Sci., 25, 257, 10.1016/S0968-0004(00)01595-4

Ono, 2000, The p38 signal transduction pathway: activation and function, Cell. Signalling, 12, 1, 10.1016/S0898-6568(99)00071-6

Kyriakis, 2001, Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation, Physiol. Rev., 81, 807, 10.1152/physrev.2001.81.2.807

Cuenda, 2007, p38 MAP-kinases pathway regulation, function and role in human diseases, Biochim. Biophys. Acta, 1773, 1358, 10.1016/j.bbamcr.2007.03.010

Han, 1994, A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells, Science, 265, 808, 10.1126/science.7914033

Lee, 1994, A protein kinase involved in the regulation of inflammatory cytokine biosynthesis, Nature, 372, 739, 10.1038/372739a0

Rouse, 1994, A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins, Cell, 78, 1027, 10.1016/0092-8674(94)90277-1

Freshney, 1994, Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27, Cell, 78, 1039, 10.1016/0092-8674(94)90278-X

Jiang, 1996, Characterization of the structure and function of a new mitogen-activated protein kinase (p38β), J. Biol. Chem., 271, 17920, 10.1074/jbc.271.30.17920

Lechner, 1996, ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation, Proc. Natl. Acad. Sci. U.S.A., 93, 4355, 10.1073/pnas.93.9.4355

Mertens, 1996, SAP kinase-3, a new member of the family of mammalian stress-activated protein kinases, FEBS Lett., 383, 273, 10.1016/0014-5793(96)00255-4

Goedert, 1997, 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., 16, 3563, 10.1093/emboj/16.12.3563

Jiang, 1997, Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38δ, J. Biol. Chem., 272, 30122, 10.1074/jbc.272.48.30122

Enslen, 1998, Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6, J. Biol. Chem., 273, 1741, 10.1074/jbc.273.3.1741

Sabio, 2005, p38γ regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP, EMBO J., 24, 1134, 10.1038/sj.emboj.7600578

Casar, 2007, Mxi2 promotes stimulus-independent ERK nuclear translocation, EMBO J., 26, 635, 10.1038/sj.emboj.7601523

Yagasaki, 2004, Exip, a splicing variant of p38α, participates in interleukin-1 receptor proximal complex and downregulates NF-κB pathway, FEBS Lett., 575, 136, 10.1016/j.febslet.2004.08.050

Wrobleski, 2005, Structural comparison of p38 inhibitor–protein complexes: a review of recent p38 inhibitors having unique binding interactions, Curr. Top. Med. Chem., 5, 1005, 10.2174/1568026054985894

ter Haar, 2007, Crystal structure of the p38α–MAPKAP kinase 2 heterodimer, J. Biol. Chem., 282, 9733, 10.1074/jbc.M611165200

White, 2007, Molecular basis of MAPK-activated protein kinase 2:p38 assembly, Proc. Natl. Acad. Sci. U.S.A., 104, 6353, 10.1073/pnas.0701679104

Patel, 2009, The three-dimensional structure of MAP kinase p38β: different features of the ATP-binding site in p38β compared with p38α, Acta Crystallogr. Sect. D Biol. Crystallogr., 65, 777, 10.1107/S090744490901600X

Bellon, 1999, The structure of phosphorylated p38γ is monomeric and reveals a conserved activation-loop conformation, Structure, 7, 1057, 10.1016/S0969-2126(99)80173-7

Alonso, 2000, Differential activation of p38 mitogen-activated protein kinase isoforms depending on signal strength, J. Biol. Chem., 275, 40641, 10.1074/jbc.M007835200

Doza, 1995, 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, FEBS Lett., 364, 223, 10.1016/0014-5793(95)00346-B

Brancho, 2003, Mechanism of p38 MAP kinase activation in vivo, Genes Dev., 17, 1969, 10.1101/gad.1107303

Zhang, 2007, Novel strategies for inhibition of the p38 MAPK pathway, Trends Pharmacol. Sci., 28, 286, 10.1016/j.tips.2007.04.008

Remy, 2010, Differential activation of p38MAPK isoforms by MKK6 and MKK3, Cell. Signalling, 22, 660, 10.1016/j.cellsig.2009.11.020

Min, 2009, The structure of the MAP2K MEK6 reveals an autoinhibitory dimer, Structure, 17, 96, 10.1016/j.str.2008.11.007

Cuevas, 2007, Role of mitogen-activated protein kinase kinase kinases in signal integration, Oncogene, 26, 3159, 10.1038/sj.onc.1210409

Zhuang, 2006, Regulation of Drosophila p38 activation by specific MAP2 kinase and MAP3 kinase in response to different stimuli, Cell. Signalling, 18, 441, 10.1016/j.cellsig.2005.05.013

Dolado, 2007, p38α MAP kinase as a sensor of reactive oxygen species in tumorigenesis, Cancer Cell, 11, 191, 10.1016/j.ccr.2006.12.013

Matsukawa, 2004, The ASK1–MAP kinase cascades in mammalian stress response, J. Biochem. (Tokyo), 136, 261, 10.1093/jb/mvh134

Sorrentino, 2008, The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner, Nat. Cell Biol., 10, 1199, 10.1038/ncb1780

Yamashita, 2008, TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-β, Mol. Cell, 31, 918, 10.1016/j.molcel.2008.09.002

Matsuzawa, 2008, Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex, Science, 321, 663, 10.1126/science.1157340

Salvador, 2005, Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases, Nat. Immunol., 6, 390, 10.1038/ni1177

Salvador, 2005, The autoimmune suppressor Gadd45α inhibits the T cell alternative p38 activation pathway, Nat. Immunol., 6, 396, 10.1038/ni1176

Jirmanova, 2009, Genetic disruption of p38α Tyr323 phosphorylation prevents T-cell receptor-mediated p38α activation and impairs interferon-γ production, Blood, 113, 2229, 10.1182/blood-2008-04-153304

Ge, 2002, MAPKK-independent activation of p38α mediated by TAB1-dependent autophosphorylation of p38α, Science, 295, 1291, 10.1126/science.1067289

Zhou, 2006, Determinants that control the specific interactions between TAB1 and p38α, Mol. Cell. Biol., 26, 3824, 10.1128/MCB.26.10.3824-3834.2006

Cheung, 2003, Feedback control of the protein kinase TAK1 by SAPK2a/p38α, EMBO J., 22, 5793, 10.1093/emboj/cdg552

Tanno, 2003, Diverse mechanisms of myocardial p38 mitogen-activated protein kinase activation: evidence for MKK-independent activation by a TAB1-associated mechanism contributing to injury during myocardial ischemia, Circ. Res., 93, 254, 10.1161/01.RES.0000083490.43943.85

Li, 2005, AMP-activated protein kinase activates p38 mitogen-activated protein kinase by increasing recruitment of p38 MAPK to TAB1 in the ischemic heart, Circ. Res., 97, 872, 10.1161/01.RES.0000187458.77026.10

Matsuyama, 2003, Activation of discoidin domain receptor 1 facilitates the maturation of human monocyte-derived dendritic cells through the TNF receptor associated factor 6/TGF-β-activated protein kinase 1 binding protein 1β/p38α mitogen-activated protein kinase signaling cascade, J. Immunol., 171, 3520, 10.4049/jimmunol.171.7.3520

Kim, 2005, p38 MAPK autophosphorylation drives macrophage IL-12 production during intracellular infection, J. Immunol., 174, 4178, 10.4049/jimmunol.174.7.4178

Im, 2008, ATR-dependent activation of p38 MAP kinase is responsible for apoptotic cell death in cells depleted of Cdc7, J. Biol. Chem., 283, 25171, 10.1074/jbc.M802851200

Zhang, 2008, Enzymatic activity and substrate specificity of mitogen-activated protein kinase p38α in different phosphorylation states, J. Biol. Chem., 283, 26591, 10.1074/jbc.M801703200

Askari, 2009, p38 is active in vitro and in vivo when monophosphorylated on Thr180, Biochemistry, 48, 2497, 10.1021/bi900024v

Lindqvist, 2009, Wip1 confers G2 checkpoint recovery competence by counteracting p53-dependent transcriptional repression, EMBO J., 28, 3196, 10.1038/emboj.2009.246

Le Guezennec, 2010, WIP1 phosphatase at the crossroads of cancer and aging, Trends Biochem. Sci., 35, 109, 10.1016/j.tibs.2009.09.005

McAlees, 2009, Hematopoietic protein tyrosine phosphatase mediates β2-adrenergic receptor-induced regulation of p38 mitogen-activated protein kinase in B lymphocytes, Mol. Cell. Biol., 29, 675, 10.1128/MCB.01466-08

Zhu, 2007, Structural insights into the enzymatic mechanism of the pathogenic MAPK phosphothreonine lyase, Mol. Cell, 28, 899, 10.1016/j.molcel.2007.11.011

Owens, 2007, Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases, Oncogene, 26, 3203, 10.1038/sj.onc.1210412

Ko, 2009, Glutamine protects mice from lethal endotoxic shock via a rapid induction of MAPK phosphatase-1, J. Immunol., 182, 7957, 10.4049/jimmunol.0900043

Yang, 2010, Induction of MAPK phosphatase-1 by hypothermia inhibits TNF-α-induced endothelial barrier dysfunction and apoptosis, Cardiovasc. Res., 85, 520, 10.1093/cvr/cvp323

Maneechotesuwan, 2009, Suppression of GATA-3 nuclear import and phosphorylation: a novel mechanism of corticosteroid action in allergic disease, PLoS Med., 6, e1000076, 10.1371/journal.pmed.1000076

Lin, 2003, ERK1/2 achieves sustained activation by stimulating MAPK phosphatase-1 degradation via the ubiquitin–proteasome pathway, J. Biol. Chem., 278, 21534, 10.1074/jbc.M301854200

Cao, 2008, Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling, J. Exp. Med., 205, 1491, 10.1084/jem.20071728

Qian, 2009, A non-redundant role for MKP5 in limiting ROS production and preventing LPS-induced vascular injury, EMBO J., 28, 2896, 10.1038/emboj.2009.234

Good, 2009, The Ste5 scaffold directs mating signaling by catalytically unlocking the Fus3 MAP kinase for activation, Cell, 136, 1085, 10.1016/j.cell.2009.01.049

Uhlik, 2003, Rac–MEKK3–MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock, Nat. Cell Biol., 5, 1104, 10.1038/ncb1071

Morrison, 2003, Regulation of MAP kinase signaling modules by scaffold proteins in mammals, Annu. Rev. Cell Dev. Biol., 19, 91, 10.1146/annurev.cellbio.19.111401.091942

Kelkar, 2005, Role of the JIP4 scaffold protein in the regulation of mitogen-activated protein kinase signaling pathways, Mol. Cell. Biol., 25, 2733, 10.1128/MCB.25.7.2733-2743.2005

Kang, 2008, A Cdo–Bnip-2–Cdc42 signaling pathway regulates p38α/β MAPK activity and myogenic differentiation, J. Cell Biol., 182, 497, 10.1083/jcb.200801119

Oh, 2009, Cdo promotes neuronal differentiation via activation of the p38 mitogen-activated protein kinase pathway, FASEB J., 23, 2088, 10.1096/fj.08-119255

Cuenda, 1999, Stress-activated protein kinase-2/p38 and a rapamycin-sensitive pathway are required for C2C12 myogenesis, J. Biol. Chem., 274, 4341, 10.1074/jbc.274.7.4341

Tanaka, 2002, Differential involvement of p38 mitogen-activated protein kinase kinases MKK3 and MKK6 in T-cell apoptosis, EMBO Rep., 3, 785, 10.1093/embo-reports/kvf153

Galan-Moya, 2008, c-Abl activates p38 MAPK independently of its tyrosine kinase activity: implications in cisplatin-based therapy, Int. J. Cancer, 122, 289, 10.1002/ijc.23063

Marasa, 2009, Increased MKK4 abundance with replicative senescence is linked to the joint reduction of multiple microRNAs, Sci. Signaling, 2, ra69, 10.1126/scisignal.2000442

Ahn, 2009, MKK4/SEK1 is negatively regulated through a feedback loop involving the E3 ubiquitin ligase itch, J. Biol. Chem., 284, 29399, 10.1074/jbc.M109.044958

Ronkina, 2007, The mitogen-activated protein kinase (MAPK)-activated protein kinases MK2 and MK3 cooperate in stimulation of tumor necrosis factor biosynthesis and stabilization of p38 MAPK, Mol. Cell. Biol., 27, 170, 10.1128/MCB.01456-06

Sudo, 2005, p38 mitogen-activated protein kinase plays a key role in regulating MAPKAPK2 expression, Biochem. Biophys. Res. Commun., 337, 415, 10.1016/j.bbrc.2005.09.063

Peregrin, 2006, Phosphorylation of p38 by GRK2 at the docking groove unveils a novel mechanism for inactivating p38MAPK, Curr. Biol., 16, 2042, 10.1016/j.cub.2006.08.083

Chopra, 2003, Anthrax lethal factor proteolysis and inactivation of MAPK kinase, J. Biol. Chem., 278, 9402, 10.1074/jbc.M211262200

Mukherjee, 2006, Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation, Science, 312, 1211, 10.1126/science.1126867

Raingeaud, 1995, Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine, J. Biol. Chem., 270, 7420, 10.1074/jbc.270.13.7420

Ben-Levy, 1998, Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2, Curr. Biol., 8, 1049, 10.1016/S0960-9822(98)70442-7

Wood, 2009, Nuclear localization of p38 MAPK in response to DNA damage, Int. J. Biol. Sci., 5, 428, 10.7150/ijbs.5.428

Engel, 1998, Leptomycin B-sensitive nuclear export of MAPKAP kinase 2 is regulated by phosphorylation, EMBO J., 17, 3363, 10.1093/emboj/17.12.3363

Lu, 2006, TAB-1 modulates intracellular localization of p38 MAP kinase and downstream signaling, J. Biol. Chem., 281, 6087, 10.1074/jbc.M507610200

Reynolds, 2000, Phosphorylation sites on tau identified by nanoelectrospray mass spectrometry: differences in vitro between the mitogen-activated protein kinases ERK2, c-Jun N-terminal kinase and p38, and glycogen synthase kinase-3β, J. Neurochem., 74, 1587, 10.1046/j.1471-4159.2000.0741587.x

Gao, 2009, Phosphorylation-independent regulation of Atf1-promoted meiotic recombination by stress-activated, p38 kinase Spc1 of fission yeast, PLoS ONE, 4, e5533, 10.1371/journal.pone.0005533

Alepuz, 2003, Osmostress-induced transcription by Hot1 depends on a Hog1-mediated recruitment of the RNA Pol II, EMBO J., 22, 2433, 10.1093/emboj/cdg243

de Nadal, 2010, Multilayered control of gene expression by stress-activated protein kinases, EMBO J., 29, 4, 10.1038/emboj.2009.346

Fan, 2005, A novel role of p38α MAPK in mitotic progression independent of its kinase activity, Cell Cycle, 4, 1616, 10.4161/cc.4.11.2125

Cheung, 2008, AMP-activated protein kinase and p38 MAPK activate O-GlcNAcylation of neuronal proteins during glucose deprivation, J. Biol. Chem., 283, 13009, 10.1074/jbc.M801222200

Tang, 2005, Essential role of p38γ in K-Ras transformation independent of phosphorylation, J. Biol. Chem., 280, 23910, 10.1074/jbc.M500699200

Tanoue, 2000, A conserved docking motif in MAP kinases common to substrates, activators and regulators, Nat. Cell Biol., 2, 110, 10.1038/35000065

Enslen, 2001, Regulation of MAP kinases by docking domains, Biol. Cell, 93, 5, 10.1016/S0248-4900(01)01156-X

Biondi, 2003, Signalling specificity of Ser/Thr protein kinases through docking-site-mediated interactions, Biochem. J., 372, 1, 10.1042/bj20021641

Mayor, 2007, Interfering with MAP kinase docking interactions: implications and perspective for the p38 route, Cell Cycle, 6, 528, 10.4161/cc.6.5.3920

Chang, 2002, Crystal structures of MAP kinase p38 complexed to the docking sites on its nuclear substrate MEF2A and activator MKK3b, Mol. Cell, 9, 1241, 10.1016/S1097-2765(02)00525-7

Roux, 2004, ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions, Microbiol. Mol. Biol. Rev., 68, 320, 10.1128/MMBR.68.2.320-344.2004

Bardwell, 2009, Selectivity of docking sites in MAPK kinases, J. Biol. Chem., 284, 13165, 10.1074/jbc.M900080200

Hasegawa, 1999, Stress-activated protein kinase-3 interacts with the PDZ domain of α1-syntrophin: a mechanism for specific substrate recognition, J. Biol. Chem., 274, 12626, 10.1074/jbc.274.18.12626

Davidson, 2004, Discovery and characterization of a substrate selective p38α inhibitor, Biochemistry, 43, 11658, 10.1021/bi0495073

Arthur, 2008, MSK activation and physiological roles, Front. Biosci., 13, 5866, 10.2741/3122

Soloaga, 2003, MSK2 and MSK1 mediate the mitogen- and stress-induced phosphorylation of histone H3 and HMG-14, EMBO J., 22, 2788, 10.1093/emboj/cdg273

Llanos, 2009, MSK2 inhibits p53 activity in the absence of stress, Sci. Signaling, 2, ra57, 10.1126/scisignal.2000205

Shi, 2002, In the cellular garden of forking paths: how p38 MAPKs signal for downstream assistance, Biol. Chem., 383, 1519, 10.1515/BC.2002.173

Mahalingam, 2001, Phosphorylation of mammalian eIF4E by Mnk1 and Mnk2: tantalizing prospects for a role in translation, Prog. Mol. Subcell. Biol., 27, 132

Zeng, 2008, Phosphorylation of Argonaute 2 at serine-387 facilitates its localization to processing bodies, Biochem. J., 413, 429, 10.1042/BJ20080599

Kundu, 2009, A TNF- and c-Cbl-dependent FLIPS-degradation pathway and its function in Mycobacterium tuberculosis-induced macrophage apoptosis, Nat. Immunol., 10, 918, 10.1038/ni.1754

Khurana, 2006, Regulation of the ring finger E3 ligase Siah2 by p38 MAPK, J. Biol. Chem., 281, 35316, 10.1074/jbc.M606568200

Swat, 2009, Cell density-dependent inhibition of epidermal growth factor receptor signaling by p38α mitogen-activated protein kinase via Sprouty2 downregulation, Mol. Cell. Biol., 29, 3332, 10.1128/MCB.01955-08

Webber, 2010, Coordinated regulation of autophagy by p38α MAPK through mAtg9 and p38IP, EMBO J., 29, 27, 10.1038/emboj.2009.321

Cavalli, 2001, The stress-induced MAP kinase p38 regulates endocytic trafficking via the GDI:Rab5 complex, Mol. Cell, 7, 421, 10.1016/S1097-2765(01)00189-7

Mace, 2005, Phosphorylation of EEA1 by p38 MAP kinase regulates μ opioid receptor endocytosis, EMBO J., 24, 3235, 10.1038/sj.emboj.7600799

Zwang, 2006, p38 MAP kinase mediates stress-induced internalization of EGFR: implications for cancer chemotherapy, EMBO J., 25, 4195, 10.1038/sj.emboj.7601297

Pinglong, 2010, Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor-dependent cell proliferation, Mol. Cell, 37, 551, 10.1016/j.molcel.2010.01.034

Sorensen, 2008, Phosphorylation of fibroblast growth factor (FGF) receptor 1 at Ser777 by p38 mitogen-activated protein kinase regulates translocation of exogenous FGF1 to the cytosol and nucleus, Mol. Cell. Biol., 28, 4129, 10.1128/MCB.02117-07

Lafarga, 2009, p38 Mitogen-activated protein kinase- and HuR-dependent stabilization of p21Cip1 mRNA mediates the G1/S checkpoint, Mol. Cell. Biol., 29, 4341, 10.1128/MCB.00210-09

Perdiguero, 2008, Transcriptional regulation by the p38 MAPK signalling pathway in mammalian cells, Top. Curr. Genet., 20, 51, 10.1007/4735_2007_0256

Geest, 2009, p38 MAP kinase inhibits neutrophil development through phosphorylation of C/EBPα on serine 21, Stem Cells, 27, 2271, 10.1002/stem.152

Adam, 2009, Computational identification of a p38SAPK-regulated transcription factor network required for tumor cell quiescence, Cancer Res., 69, 5664, 10.1158/0008-5472.CAN-08-3820

Corre, 2009, Target gene specificity of USF-1 is directed via p38-mediated phosphorylationdependent acetylation, J. Biol. Chem., 284, 18851, 10.1074/jbc.M808605200

Saccani, 2002, p38-Dependent marking of inflammatory genes for increased NF-κB recruitment, Nat. Immunol., 3, 69, 10.1038/ni748

Zhao, 2008, The p38 mitogen-activated protein kinase augments nucleotide excision repair by mediating DDB2 degradation and chromatin relaxation, J. Biol. Chem., 283, 32553, 10.1074/jbc.M803963200

Rampalli, 2007, p38 MAPK signaling regulates recruitment of Ash2L-containing methyltransferase complexes to specific genes during differentiation, Nat. Struct. Mol. Biol., 14, 1150, 10.1038/nsmb1316

Rao, 2009, RNF2 is the target for phosphorylation by the p38 MAPK and ERK signaling pathways, Proteomics, 9, 2776, 10.1002/pmic.200800847

Lluis, 2006, Regulation of skeletal muscle gene expression by p38 MAP kinases, Trends Cell Biol., 16, 36, 10.1016/j.tcb.2005.11.002

Barski, 2007, High-resolution profiling of histone methylations in the human genome, Cell, 129, 823, 10.1016/j.cell.2007.05.009

Cui, 2009, Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation, Cell Stem Cell, 4, 80, 10.1016/j.stem.2008.11.011

Wong, 2007, The chromatin remodeling protein, SRCAP, is critical for deposition of the histone variant H2A.Z at promoters, J. Biol. Chem., 282, 26132, 10.1074/jbc.M703418200

Cuadrado, 2007, A new p38 MAP kinase-regulated transcriptional coactivator that stimulates p53-dependent apoptosis, EMBO J., 26, 2115, 10.1038/sj.emboj.7601657

Lafarga, 2007, p18Hamlet mediates different p53-dependent responses to DNA-damage inducing agents, Cell Cycle, 6, 2319, 10.4161/cc.6.19.4741

Cuadrado, 2010, Essential role of p18Hamlet/SRCAP-mediated histone H2A.Z chromatin incorporation in muscle differentiation, EMBO J., 10.1038/emboj.2010.85

Junttila, 2008, Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival, FASEB J., 22, 954, 10.1096/fj.06-7859rev

Wagner, 2009, Signal integration by JNK and p38 MAPK pathways in cancer development, Nat. Rev. Cancer, 9, 537, 10.1038/nrc2694

Vermeulen, 2003, Transcriptional activation of the NF-κB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1), EMBO J., 22, 1313, 10.1093/emboj/cdg139

Kefaloyianni, 2006, ERK1/2 and p38-MAPK signalling pathways, through MSK1, are involved in NF-κB transactivation during oxidative stress in skeletal myoblasts, Cell. Signalling, 18, 2238, 10.1016/j.cellsig.2006.05.004

Chew, 2009, WIP1 phosphatase is a negative regulator of NF-κB signalling, Nat. Cell Biol., 11, 659, 10.1038/ncb1873

Thornton, 2008, Phosphorylation by p38 MAPK as an alternative pathway for GSK3β inactivation, Science, 320, 667, 10.1126/science.1156037

Abell, 2007, MEKK4 stimulation of p38 and JNK activity is negatively regulated by GSK3β, J. Biol. Chem., 282, 30476, 10.1074/jbc.M705783200

Yuan, 2003, AKT2 inhibition of cisplatin-induced JNK/p38 and Bax activation by phosphorylation of ASK1: implication of AKT2 in chemoresistance, J. Biol. Chem., 278, 23432, 10.1074/jbc.M302674200

Kim, 2009, Akt2, but not Akt1, is required for cell survival by inhibiting activation of JNK and p38 after UV irradiation, Oncogene, 28, 1241, 10.1038/onc.2008.487

Zuluaga, 2007, Negative regulation of Akt activity by p38α MAP kinase in cardiomyocytes involves membrane localization of PP2A through interaction with caveolin-1, Cell. Signalling, 19, 62, 10.1016/j.cellsig.2006.05.032

Seimon, 2009, Macrophage deficiency of p38α MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice, J. Clin. Invest., 119, 886

Wu, 2007, Hsp27 regulates Akt activation and polymorphonuclear leukocyte apoptosis by scaffolding MK2 to Akt signal complex, J. Biol. Chem., 282, 21598, 10.1074/jbc.M611316200

Marshall, 1995, Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation, Cell, 80, 179, 10.1016/0092-8674(95)90401-8

Dolado, 2008, Regulation of tumorigenesis by p38α MAP kinase, Top. Curr. Genet., 20, 99, 10.1007/4735_2007_0245

Haq, 2002, Constitutive p38HOG mitogen-activated protein kinase activation induces permanent cell cycle arrest and senescence, Cancer Res., 62, 5076

Puri, 2000, Induction of terminal differentiation by constitutive activation of p38 MAP kinase in human rhabdomyosarcoma cells, Genes Dev., 14, 574, 10.1101/gad.14.5.574

Ambrosino, 2003, Negative feedback regulation of MKK6 mRNA stability by p38α mitogen-activated protein kinase, Mol. Cell. Biol., 23, 370, 10.1128/MCB.23.1.370-381.2003

Adams, 2000, Essential role of p38α MAP kinase in placental but not embryonic cardiovascular development, Mol. Cell, 6, 109, 10.1016/S1097-2765(05)00014-6

Mudgett, 2000, Essential role for p38α mitogen-activated protein kinase in placental angiogenesis, Proc. Natl. Acad. Sci. U.S.A., 97, 10454, 10.1073/pnas.180316397

Tamura, 2000, Requirement for p38α in erythropoietin expression: a role for stress kinases in erythropoiesis, Cell, 102, 221, 10.1016/S0092-8674(00)00027-1

Lu, 1999, Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice, EMBO J., 18, 1845, 10.1093/emboj/18.7.1845

Ventura, 2007, p38α MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation, Nat. Genet., 39, 750, 10.1038/ng2037

Hui, 2007, p38α suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway, Nat. Genet., 39, 741, 10.1038/ng2033

Engel, 2005, p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes, Genes Dev., 19, 1175, 10.1101/gad.1306705

Kang, 2008, Macrophage deletion of p38α partially impairs lipopolysaccharide-induced cellular activation, J. Immunol., 180, 5075, 10.4049/jimmunol.180.7.5075

Kim, 2008, The kinase p38α serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression, Nat. Immunol., 9, 1019, 10.1038/ni.1640

Sakurai, 2008, Hepatocyte necrosis induced by oxidative stress and IL-1α release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis, Cancer Cell, 14, 156, 10.1016/j.ccr.2008.06.016

Wong, 2009, p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age, Dev. Cell, 17, 142, 10.1016/j.devcel.2009.05.009

Beardmore, 2005, Generation and characterization of p38β (MAPK11) gene-targeted mice, Mol. Cell. Biol., 25, 10454, 10.1128/MCB.25.23.10454-10464.2005

Sumara, 2009, Regulation of PKD by the MAPK p38δ in insulin secretion and glucose homeostasis, Cell, 136, 235, 10.1016/j.cell.2008.11.018

Schindler, 2009, p38δ Mitogen-activated protein kinase is essential for skin tumor development in mice, Cancer Res., 69, 4648, 10.1158/0008-5472.CAN-08-4455

Gillespie, 2009, p38γ-dependent gene silencing restricts entry into the myogenic differentiation program, J. Cell Biol., 187, 991, 10.1083/jcb.200907037

Kumar, 2003, p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases, Nat. Rev. Drug Discov., 2, 717, 10.1038/nrd1177

Coulthard, 2009, p38MAPK: stress responses from molecular mechanisms to therapeutics, Trends Mol. Med., 15, 369, 10.1016/j.molmed.2009.06.005

Cohen, 1997, The search for physiological substrates of MAP and SAP kinases in mammalian cells, Trends Cell Biol., 7, 353, 10.1016/S0962-8924(97)01105-7

Eyers, 1998, Conversion of SB 203580-insensitive MAP kinase family members to drug-sensitive forms by a single amino-acid substitution, Chem. Biol., 5, 321, 10.1016/S1074-5521(98)90170-3

Gum, 1998, 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., 273, 15605, 10.1074/jbc.273.25.15605

Godl, 2003, An efficient proteomics method to identify the cellular targets of protein kinase inhibitors, Proc. Natl. Acad. Sci. U.S.A., 100, 15434, 10.1073/pnas.2535024100

Fabian, 2005, A small molecule–kinase interaction map for clinical kinase inhibitors, Nat. Biotechnol., 23, 329, 10.1038/nbt1068

Xing, 2009, Structural bioinformatics-based prediction of exceptional selectivity of p38 MAP kinase inhibitor PH-797804, Biochemistry, 48, 6402, 10.1021/bi900655f

Pargellis, 2002, Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site, Nat. Struct. Biol., 9, 268, 10.1038/nsb770

Perry, 2009, p38α MAP kinase C-terminal domain binding pocket characterized by crystallographic and computational analyses, J. Mol. Biol., 391, 1, 10.1016/j.jmb.2009.06.005

Mayer, 2006, p38 MAP kinase inhibitors: a future therapy for inflammatory diseases, Drug Discov. Today, 3, 49

Sy, 2008, Sustained release of a p38 inhibitor from non-inflammatory microspheres inhibits cardiac dysfunction, Nat. Mater., 7, 863, 10.1038/nmat2299

Gaestel, 2009, Peptides as signaling inhibitors for mammalian MAP kinase cascades, Curr. Pharm. Des., 15, 2471, 10.2174/138161209788682299