Mitogen-activated protein kinase 14

NameMitogen-activated protein kinase 14
Synonyms
  • 2.7.11.24
  • CSAID-binding protein
  • CSBP
  • CSBP1
  • CSBP2
  • CSPB1
  • Cytokine suppressive anti-inflammatory drug-binding protein
  • MAP kinase 14
  • MAP kinase MXI2
  • MAP kinase p38 alpha
  • MAX-interacting protein 2
  • Mitogen-activated protein kinase p38 alpha
  • MXI2
  • SAPK2A
  • Stress-activated protein kinase 2a
Gene NameMAPK14
OrganismHuman
Amino acid sequence
>lcl|BSEQ0002029|Mitogen-activated protein kinase 14
MSQERPTFYRQELNKTIWEVPERYQNLSPVGSGAYGSVCAAFDTKTGLRVAVKKLSRPFQ
SIIHAKRTYRELRLLKHMKHENVIGLLDVFTPARSLEEFNDVYLVTHLMGADLNNIVKCQ
KLTDDHVQFLIYQILRGLKYIHSADIIHRDLKPSNLAVNEDCELKILDFGLARHTDDEMT
GYVATRWYRAPEIMLNWMHYNQTVDIWSVGCIMAELLTGRTLFPGTDHIDQLKLILRLVG
TPGAELLKKISSESARNYIQSLTQMPKMNFANVFIGANPLAVDLLEKMLVLDSDKRITAA
QALAHAYFAQYHDPDDEPVADPYDQSFESRDLLIDEWKSLTYDEVISFVPPPLDQEEMES
Number of residues360
Molecular Weight41292.885
Theoretical pI5.58
GO Classification
Functions
  • MAP kinase activity
  • enzyme binding
  • NFAT protein binding
  • ATP binding
  • MAP kinase kinase activity
  • protein phosphatase binding
  • protein serine/threonine kinase activity
Processes
  • cellular response to ionizing radiation
  • positive regulation of interleukin-12 secretion
  • MyD88-dependent toll-like receptor signaling pathway
  • cell surface receptor signaling pathway
  • chemotaxis
  • positive regulation of cyclase activity
  • MyD88-independent toll-like receptor signaling pathway
  • positive regulation of reactive oxygen species metabolic process
  • platelet activation
  • p38MAPK cascade
  • regulation of sequence-specific DNA binding transcription factor activity
  • intracellular signal transduction
  • cellular response to lipopolysaccharide
  • stress-induced premature senescence
  • stress-activated MAPK cascade
  • movement of cell or subcellular component
  • gene expression
  • toll-like receptor 10 signaling pathway
  • organelle organization
  • 3'-UTR-mediated mRNA stabilization
  • toll-like receptor 2 signaling pathway
  • mitochondrion organization
  • regulation of cytokine production involved in inflammatory response
  • toll-like receptor 3 signaling pathway
  • transcription, DNA-templated
  • toll-like receptor 4 signaling pathway
  • activation of MAPK activity
  • innate immune response
  • toll-like receptor 5 signaling pathway
  • positive regulation of gene expression
  • muscle cell differentiation
  • toll-like receptor 9 signaling pathway
  • peptidyl-serine phosphorylation
  • positive regulation of muscle cell differentiation
  • toll-like receptor signaling pathway
  • signal transduction
  • regulation of transcription from RNA polymerase II promoter
  • signal transduction in response to DNA damage
  • toll-like receptor TLR1
  • apoptotic process
  • toll-like receptor TLR6
  • positive regulation of myotube differentiation
  • cellular response to vascular endothelial growth factor stimulus
  • neurotrophin TRK receptor signaling pathway
  • TRIF-dependent toll-like receptor signaling pathway
  • blood coagulation
  • positive regulation of erythrocyte differentiation
  • regulation of mRNA stability
  • Ras protein signal transduction
  • cellular response to virus
  • positive regulation of myoblast fusion
  • osteoclast differentiation
  • vascular endothelial growth factor receptor signaling pathway
  • positive regulation of myoblast differentiation
Components
  • cytosol
  • extracellular exosome
  • nucleoplasm
  • cytoplasm
  • nucleus
General FunctionProtein serine/threonine kinase activity
Specific FunctionSerine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113'.
Pfam Domain Function
Transmembrane RegionsNot Available
GenBank Protein ID603917
UniProtKB IDQ16539
UniProtKB Entry NameMK14_HUMAN
Cellular LocationCytoplasm
Gene sequence
>lcl|BSEQ0021282|Mitogen-activated protein kinase 14 (MAPK14)
ATGTCTCAGGAGAGGCCCACGTTCTACCGGCAGGAGCTGAACAAGACAATCTGGGAGGTG
CCCGAGCGTTACCAGAACCTGTCTCCAGTGGGCTCTGGCGCCTATGGCTCTGTGTGTGCT
GCTTTTGACACAAAAACGGGGTTACGTGTGGCAGTGAAGAAGCTCTCCAGACCATTTCAG
TCCATCATTCATGCGAAAAGAACCTACAGAGAACTGCGGTTACTTAAACATATGAAACAT
GAAAATGTGATTGGTCTGTTGGACGTTTTTACACCTGCAAGGTCTCTGGAGGAATTCAAT
GATGTGTATCTGGTGACCCATCTCATGGGGGCAGATCTGAACAACATTGTGAAATGTCAG
AAGCTTACAGATGACCATGTTCAGTTCCTTATCTACCAAATTCTCCGAGGTCTAAAGTAT
ATACATTCAGCTGACATAATTCACAGGGACCTAAAACCTAGTAATCTAGCTGTGAATGAA
GACTGTGAGCTGAAGATTCTGGATTTTGGACTGGCTCGGCACACAGATGATGAAATGACA
GGCTACGTGGCCACTAGGTGGTACAGGGCTCCTGAGATCATGCTGAACTGGATGCATTAC
AACCAGACAGTTGATATTTGGTCAGTGGGATGCATAATGGCCGAGCTGTTGACTGGAAGA
ACATTGTTTCCTGGTACAGACCATATTAACCAGCTTCAGCAGATTATGCGTCTGACAGGA
ACACCCCCCGCTTATCTCATTAACAGGATGCCAAGCCATGAGGCAAGAAACTATATTCAG
TCTTTGACTCAGATGCCGAAGATGAACTTTGCGAATGTATTTATTGGTGCCAATCCCCTG
GCTGTCGACTTGCTGGAGAAGATGCTTGTATTGGACTCAGATAAGAGAATTACAGCGGCC
CAAGCCCTTGCACATGCCTACTTTGCTCAGTACCACGATCCTGATGATGAACCAGTGGCC
GATCCTTATGATCAGTCCTTTGAAAGCAGGGACCTCCTTATAGATGAGTGGAAAAGCCTG
ACCTATGATGAAGTCATCAGCTTTGTGCCACCACCCCTTGACCAAGAAGAGATGGAGTCC
TGA
GenBank Gene IDL35263
GeneCard IDNot Available
GenAtlas IDMAPK14
HGNC IDHGNC:6876
Chromosome Location6
Locus6p21.3-p21.2
References
  1. Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Heys JR, Landvatter SW, et al.: A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994 Dec 22-29;372(6508):739-46. 7997261
  2. Han J, Richter B, Li Z, Kravchenko V, Ulevitch RJ: Molecular cloning of human p38 MAP kinase. Biochim Biophys Acta. 1995 Mar 16;1265(2-3):224-7. 7696354
  3. Zervos AS, Faccio L, Gatto JP, Kyriakis JM, Brent R: Mxi2, a mitogen-activated protein kinase that recognizes and phosphorylates Max protein. Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10531-4. 7479834
  4. Herbison CE, Sayer DC, Bellgard M, Allcock RJ, Christiansen FT, Price P: Structure and polymorphism of two stress-activated protein kinase genes centromeric of the MHC: SAPK2a and SAPK4. DNA Seq. 1999;10(4-5):229-43. 10727080
  5. Sudo T, Yagasaki Y, Hama H, Watanabe N, Osada H: Exip, a new alternative splicing variant of p38 alpha, can induce an earlier onset of apoptosis in HeLa cells. Biochem Biophys Res Commun. 2002 Mar 8;291(4):838-43. 11866441
  6. Wang P, Yu P, Gao P, Shi T, Ma D: Discovery of novel human transcript variants by analysis of intronic single-block EST with polyadenylation site. BMC Genomics. 2009 Nov 12;10:518. doi: 10.1186/1471-2164-10-518. 19906316
  7. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. 14702039
  8. Mungall AJ, Palmer SA, Sims SK, Edwards CA, Ashurst JL, Wilming L, Jones MC, Horton R, Hunt SE, Scott CE, Gilbert JG, Clamp ME, Bethel G, Milne S, Ainscough R, Almeida JP, Ambrose KD, Andrews TD, Ashwell RI, Babbage AK, Bagguley CL, Bailey J, Banerjee R, Barker DJ, Barlow KF, Bates K, Beare DM, Beasley H, Beasley O, Bird CP, Blakey S, Bray-Allen S, Brook J, Brown AJ, Brown JY, Burford DC, Burrill W, Burton J, Carder C, Carter NP, Chapman JC, Clark SY, Clark G, Clee CM, Clegg S, Cobley V, Collier RE, Collins JE, Colman LK, Corby NR, Coville GJ, Culley KM, Dhami P, Davies J, Dunn M, Earthrowl ME, Ellington AE, Evans KA, Faulkner L, Francis MD, Frankish A, Frankland J, French L, Garner P, Garnett J, Ghori MJ, Gilby LM, Gillson CJ, Glithero RJ, Grafham DV, Grant M, Gribble S, Griffiths C, Griffiths M, Hall R, Halls KS, Hammond S, Harley JL, Hart EA, Heath PD, Heathcott R, Holmes SJ, Howden PJ, Howe KL, Howell GR, Huckle E, Humphray SJ, Humphries MD, Hunt AR, Johnson CM, Joy AA, Kay M, Keenan SJ, Kimberley AM, King A, Laird GK, Langford C, Lawlor S, Leongamornlert DA, Leversha M, Lloyd CR, Lloyd DM, Loveland JE, Lovell J, Martin S, Mashreghi-Mohammadi M, Maslen GL, Matthews L, McCann OT, McLaren SJ, McLay K, McMurray A, Moore MJ, Mullikin JC, Niblett D, Nickerson T, Novik KL, Oliver K, Overton-Larty EK, Parker A, Patel R, Pearce AV, Peck AI, Phillimore B, Phillips S, Plumb RW, Porter KM, Ramsey Y, Ranby SA, Rice CM, Ross MT, Searle SM, Sehra HK, Sheridan E, Skuce CD, Smith S, Smith M, Spraggon L, Squares SL, Steward CA, Sycamore N, Tamlyn-Hall G, Tester J, Theaker AJ, Thomas DW, Thorpe A, Tracey A, Tromans A, Tubby B, Wall M, Wallis JM, West AP, White SS, Whitehead SL, Whittaker H, Wild A, Willey DJ, Wilmer TE, Wood JM, Wray PW, Wyatt JC, Young L, Younger RM, Bentley DR, Coulson A, Durbin R, Hubbard T, Sulston JE, Dunham I, Rogers J, Beck S: The DNA sequence and analysis of human chromosome 6. Nature. 2003 Oct 23;425(6960):805-11. 14574404
  9. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. 15489334
  10. Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J: Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides. Nat Biotechnol. 2003 May;21(5):566-9. Epub 2003 Mar 31. 12665801
  11. Freshney NW, Rawlinson L, Guesdon F, Jones E, Cowley S, Hsuan J, Saklatvala J: Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell. 1994 Sep 23;78(6):1039-49. 7923354
  12. Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ: Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem. 1995 Mar 31;270(13):7420-6. 7535770
  13. Kumar S, McLaughlin MM, McDonnell PC, Lee JC, Livi GP, Young PR: Human mitogen-activated protein kinase CSBP1, but not CSBP2, complements a hog1 deletion in yeast. J Biol Chem. 1995 Dec 8;270(49):29043-6. 7493921
  14. Raingeaud J, Whitmarsh AJ, Barrett T, Derijard B, Davis RJ: MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol. 1996 Mar;16(3):1247-55. 8622669
  15. Deak M, Clifton AD, Lucocq LM, Alessi DR: Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J. 1998 Aug 3;17(15):4426-41. 9687510
  16. Enslen H, Raingeaud J, Davis RJ: Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. J Biol Chem. 1998 Jan 16;273(3):1741-8. 9430721
  17. Pierrat B, Correia JS, Mary JL, Tomas-Zuber M, Lesslauer W: RSK-B, a novel ribosomal S6 kinase family member, is a CREB kinase under dominant control of p38alpha mitogen-activated protein kinase (p38alphaMAPK). J Biol Chem. 1998 Nov 6;273(45):29661-71. 9792677
  18. Tanoue T, Moriguchi T, Nishida E: Molecular cloning and characterization of a novel dual specificity phosphatase, MKP-5. J Biol Chem. 1999 Jul 9;274(28):19949-56. 10391943
  19. Zhao M, New L, Kravchenko VV, Kato Y, Gram H, di Padova F, Olson EN, Ulevitch RJ, Han J: Regulation of the MEF2 family of transcription factors by p38. Mol Cell Biol. 1999 Jan;19(1):21-30. 9858528
  20. Yang SH, Galanis A, Sharrocks AD: Targeting of p38 mitogen-activated protein kinases to MEF2 transcription factors. Mol Cell Biol. 1999 Jun;19(6):4028-38. 10330143
  21. Tamura K, Sudo T, Senftleben U, Dadak AM, Johnson R, Karin M: Requirement for p38alpha in erythropoietin expression: a role for stress kinases in erythropoiesis. Cell. 2000 Jul 21;102(2):221-31. 10943842
  22. Sanz V, Arozarena I, Crespo P: Distinct carboxy-termini confer divergent characteristics to the mitogen-activated protein kinase p38alpha and its splice isoform Mxi2. FEBS Lett. 2000 Jun 2;474(2-3):169-74. 10838079
  23. Sayed M, Kim SO, Salh BS, Issinger OG, Pelech SL: Stress-induced activation of protein kinase CK2 by direct interaction with p38 mitogen-activated protein kinase. J Biol Chem. 2000 Jun 2;275(22):16569-73. 10747897
  24. Alonso G, Ambrosino C, Jones M, Nebreda AR: Differential activation of p38 mitogen-activated protein kinase isoforms depending on signal strength. J Biol Chem. 2000 Dec 22;275(51):40641-8. 11010976
  25. Slack DN, Seternes OM, Gabrielsen M, Keyse SM: Distinct binding determinants for ERK2/p38alpha and JNK map kinases mediate catalytic activation and substrate selectivity of map kinase phosphatase-1. J Biol Chem. 2001 May 11;276(19):16491-500. Epub 2001 Jan 30. 11278799
  26. Tanoue T, Yamamoto T, Maeda R, Nishida E: A Novel MAPK phosphatase MKP-7 acts preferentially on JNK/SAPK and p38 alpha and beta MAPKs. J Biol Chem. 2001 Jul 13;276(28):26629-39. Epub 2001 May 18. 11359773
  27. Scheper GC, Morrice NA, Kleijn M, Proud CG: The mitogen-activated protein kinase signal-integrating kinase Mnk2 is a eukaryotic initiation factor 4E kinase with high levels of basal activity in mammalian cells. Mol Cell Biol. 2001 Feb;21(3):743-54. 11154262
  28. Bulavin DV, Higashimoto Y, Popoff IJ, Gaarde WA, Basrur V, Potapova O, Appella E, Fornace AJ Jr: Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase. Nature. 2001 May 3;411(6833):102-7. 11333986
  29. Ge B, Gram H, Di Padova F, Huang B, New L, Ulevitch RJ, Luo Y, Han J: MAPKK-independent activation of p38alpha mediated by TAB1-dependent autophosphorylation of p38alpha. Science. 2002 Feb 15;295(5558):1291-4. 11847341
  30. Diskin R, Askari N, Capone R, Engelberg D, Livnah O: Active mutants of the human p38alpha mitogen-activated protein kinase. J Biol Chem. 2004 Nov 5;279(45):47040-9. Epub 2004 Jul 28. 15284239
  31. Lominadze G, Rane MJ, Merchant M, Cai J, Ward RA, McLeish KR: Myeloid-related protein-14 is a p38 MAPK substrate in human neutrophils. J Immunol. 2005 Jun 1;174(11):7257-67. 15905572
  32. Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ: Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nat Biotechnol. 2005 Jan;23(1):94-101. Epub 2004 Dec 12. 15592455
  33. Salvador JM, Mittelstadt PR, Guszczynski T, Copeland TD, Yamaguchi H, Appella E, Fornace AJ Jr, Ashwell JD: Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases. Nat Immunol. 2005 Apr;6(4):390-5. Epub 2005 Feb 27. 15735648
  34. Salvador JM, Mittelstadt PR, Belova GI, Fornace AJ Jr, Ashwell JD: The autoimmune suppressor Gadd45alpha inhibits the T cell alternative p38 activation pathway. Nat Immunol. 2005 Apr;6(4):396-402. Epub 2005 Feb 27. 15735649
  35. Zohn IE, Li Y, Skolnik EY, Anderson KV, Han J, Niswander L: p38 and a p38-interacting protein are critical for downregulation of E-cadherin during mouse gastrulation. Cell. 2006 Jun 2;125(5):957-69. 16751104
  36. Zwang Y, Yarden Y: p38 MAP kinase mediates stress-induced internalization of EGFR: implications for cancer chemotherapy. EMBO J. 2006 Sep 20;25(18):4195-206. Epub 2006 Aug 24. 16932740
  37. Khurana A, Nakayama K, Williams S, Davis RJ, Mustelin T, Ronai Z: Regulation of the ring finger E3 ligase Siah2 by p38 MAPK. J Biol Chem. 2006 Nov 17;281(46):35316-26. Epub 2006 Sep 25. 17003045
  38. Fu J, Yang Z, Wei J, Han J, Gu J: Nuclear protein NP60 regulates p38 MAPK activity. J Cell Sci. 2006 Jan 1;119(Pt 1):115-23. Epub 2005 Dec 13. 16352664
  39. Qi X, Pohl NM, Loesch M, Hou S, Li R, Qin JZ, Cuenda A, Chen G: p38alpha antagonizes p38gamma activity through c-Jun-dependent ubiquitin-proteasome pathways in regulating Ras transformation and stress response. J Biol Chem. 2007 Oct 26;282(43):31398-408. Epub 2007 Aug 27. 17724032
  40. Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ: ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 2007 May 25;316(5828):1160-6. 17525332
  41. Zahedi RP, Lewandrowski U, Wiesner J, Wortelkamp S, Moebius J, Schutz C, Walter U, Gambaryan S, Sickmann A: Phosphoproteome of resting human platelets. J Proteome Res. 2008 Feb;7(2):526-34. Epub 2007 Dec 19. 18088087
  42. Daub H, Olsen JV, Bairlein M, Gnad F, Oppermann FS, Korner R, Greff Z, Keri G, Stemmann O, Mann M: Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol Cell. 2008 Aug 8;31(3):438-48. doi: 10.1016/j.molcel.2008.07.007. 18691976
  43. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP: A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7. doi: 10.1073/pnas.0805139105. Epub 2008 Jul 31. 18669648
  44. Oppermann FS, Gnad F, Olsen JV, Hornberger R, Greff Z, Keri G, Mann M, Daub H: Large-scale proteomics analysis of the human kinome. Mol Cell Proteomics. 2009 Jul;8(7):1751-64. doi: 10.1074/mcp.M800588-MCP200. Epub 2009 Apr 15. 19369195
  45. Mayya V, Lundgren DH, Hwang SI, Rezaul K, Wu L, Eng JK, Rodionov V, Han DK: Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci Signal. 2009 Aug 18;2(84):ra46. doi: 10.1126/scisignal.2000007. 19690332
  46. Webber JL, Tooze SA: Coordinated regulation of autophagy by p38alpha MAPK through mAtg9 and p38IP. EMBO J. 2010 Jan 6;29(1):27-40. doi: 10.1038/emboj.2009.321. Epub 2009 Nov 5. 19893488
  47. Reinhardt HC, Hasskamp P, Schmedding I, Morandell S, van Vugt MA, Wang X, Linding R, Ong SE, Weaver D, Carr SA, Yaffe MB: DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization. Mol Cell. 2010 Oct 8;40(1):34-49. doi: 10.1016/j.molcel.2010.09.018. 20932473
  48. Xu P, Derynck R: Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor-dependent cell proliferation. Mol Cell. 2010 Feb 26;37(4):551-66. doi: 10.1016/j.molcel.2010.01.034. 20188673
  49. Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, Brunak S, Mann M: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal. 2010 Jan 12;3(104):ra3. doi: 10.1126/scisignal.2000475. 20068231
  50. Burkard TR, Planyavsky M, Kaupe I, Breitwieser FP, Burckstummer T, Bennett KL, Superti-Furga G, Colinge J: Initial characterization of the human central proteome. BMC Syst Biol. 2011 Jan 26;5:17. doi: 10.1186/1752-0509-5-17. 21269460
  51. Pillai VB, Sundaresan NR, Samant SA, Wolfgeher D, Trivedi CM, Gupta MP: Acetylation of a conserved lysine residue in the ATP binding pocket of p38 augments its kinase activity during hypertrophy of cardiomyocytes. Mol Cell Biol. 2011 Jun;31(11):2349-63. doi: 10.1128/MCB.01205-10. Epub 2011 Mar 28. 21444723
  52. An H, Lu X, Liu D, Yarbrough WG: LZAP inhibits p38 MAPK (p38) phosphorylation and activity by facilitating p38 association with the wild-type p53 induced phosphatase 1 (WIP1). PLoS One. 2011 Jan 24;6(1):e16427. doi: 10.1371/journal.pone.0016427. 21283629
  53. Shi Y, Gaestel M: In the cellular garden of forking paths: how p38 MAPKs signal for downstream assistance. Biol Chem. 2002 Oct;383(10):1519-36. 12452429
  54. Cuadrado A, Nebreda AR: Mechanisms and functions of p38 MAPK signalling. Biochem J. 2010 Aug 1;429(3):403-17. doi: 10.1042/BJ20100323. 20626350
  55. Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014 Jan 16;96:253-62. doi: 10.1016/j.jprot.2013.11.014. Epub 2013 Nov 22. 24275569
  56. Vaca Jacome AS, Rabilloud T, Schaeffer-Reiss C, Rompais M, Ayoub D, Lane L, Bairoch A, Van Dorsselaer A, Carapito C: N-terminome analysis of the human mitochondrial proteome. Proteomics. 2015 Jul;15(14):2519-24. doi: 10.1002/pmic.201400617. Epub 2015 Jun 8. 25944712
  57. Wilson KP, Fitzgibbon MJ, Caron PR, Griffith JP, Chen W, McCaffrey PG, Chambers SP, Su MS: Crystal structure of p38 mitogen-activated protein kinase. J Biol Chem. 1996 Nov 1;271(44):27696-700. 8910361
  58. Tong L, Pav S, White DM, Rogers S, Crane KM, Cywin CL, Brown ML, Pargellis CA: A highly specific inhibitor of human p38 MAP kinase binds in the ATP pocket. Nat Struct Biol. 1997 Apr;4(4):311-6. 9095200
  59. Wang Z, Canagarajah BJ, Boehm JC, Kassisa S, Cobb MH, Young PR, Abdel-Meguid S, Adams JL, Goldsmith EJ: Structural basis of inhibitor selectivity in MAP kinases. Structure. 1998 Sep 15;6(9):1117-28. 9753691
  60. Shewchuk L, Hassell A, Wisely B, Rocque W, Holmes W, Veal J, Kuyper LF: Binding mode of the 4-anilinoquinazoline class of protein kinase inhibitor: X-ray crystallographic studies of 4-anilinoquinazolines bound to cyclin-dependent kinase 2 and p38 kinase. J Med Chem. 2000 Jan 13;43(1):133-8. 10633045
  61. Pargellis C, Tong L, Churchill L, Cirillo PF, Gilmore T, Graham AG, Grob PM, Hickey ER, Moss N, Pav S, Regan J: Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nat Struct Biol. 2002 Apr;9(4):268-72. 11896401
  62. Stelmach JE, Liu L, Patel SB, Pivnichny JV, Scapin G, Singh S, Hop CE, Wang Z, Strauss JR, Cameron PM, Nichols EA, O'Keefe SJ, O'Neill EA, Schmatz DM, Schwartz CD, Thompson CM, Zaller DM, Doherty JB: Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase. Bioorg Med Chem Lett. 2003 Jan 20;13(2):277-80. 12482439
  63. Trejo A, Arzeno H, Browner M, Chanda S, Cheng S, Comer DD, Dalrymple SA, Dunten P, Lafargue J, Lovejoy B, Freire-Moar J, Lim J, Mcintosh J, Miller J, Papp E, Reuter D, Roberts R, Sanpablo F, Saunders J, Song K, Villasenor A, Warren SD, Welch M, Weller P, Whiteley PE, Zeng L, Goldstein DM: Design and synthesis of 4-azaindoles as inhibitors of p38 MAP kinase. J Med Chem. 2003 Oct 23;46(22):4702-13. 14561090
  64. Fitzgerald CE, Patel SB, Becker JW, Cameron PM, Zaller D, Pikounis VB, O'Keefe SJ, Scapin G: Structural basis for p38alpha MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity. Nat Struct Biol. 2003 Sep;10(9):764-9. Epub 2003 Aug 3. 12897767
  65. Patel SB, Cameron PM, Frantz-Wattley B, O'Neill E, Becker JW, Scapin G: Lattice stabilization and enhanced diffraction in human p38 alpha crystals by protein engineering. Biochim Biophys Acta. 2004 Jan 14;1696(1):67-73. 14726206
  66. Sullivan JE, Holdgate GA, Campbell D, Timms D, Gerhardt S, Breed J, Breeze AL, Bermingham A, Pauptit RA, Norman RA, Embrey KJ, Read J, VanScyoc WS, Ward WH: Prevention of MKK6-dependent activation by binding to p38alpha MAP kinase. Biochemistry. 2005 Dec 20;44(50):16475-90. 16342939
  67. Tamayo N, Liao L, Goldberg M, Powers D, Tudor YY, Yu V, Wong LM, Henkle B, Middleton S, Syed R, Harvey T, Jang G, Hungate R, Dominguez C: Design and synthesis of potent pyridazine inhibitors of p38 MAP kinase. Bioorg Med Chem Lett. 2005 May 2;15(9):2409-13. 15837335
  68. Michelotti EL, Moffett KK, Nguyen D, Kelly MJ, Shetty R, Chai X, Northrop K, Namboodiri V, Campbell B, Flynn GA, Fujimoto T, Hollinger FP, Bukhtiyarova M, Springman EB, Karpusas M: Two classes of p38alpha MAP kinase inhibitors having a common diphenylether core but exhibiting divergent binding modes. Bioorg Med Chem Lett. 2005 Dec 1;15(23):5274-9. Epub 2005 Sep 19. 16169718
  69. Hartshorn MJ, Murray CW, Cleasby A, Frederickson M, Tickle IJ, Jhoti H: Fragment-based lead discovery using X-ray crystallography. J Med Chem. 2005 Jan 27;48(2):403-13. 15658854
  70. ter Haar E, Prabhakar P, Liu X, Lepre C: Crystal structure of the p38 alpha-MAPKAP kinase 2 heterodimer. J Biol Chem. 2007 Mar 30;282(13):9733-9. Epub 2007 Jan 25. 17255097
  71. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR: Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8;446(7132):153-8. 17344846