1kwp › Citations

Structure of mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 suggests a bifunctional switch that couples kinase activation with nuclear export.

Meng W, Swenson LL, Fitzgibbon MJ, Hayakawa K, Ter Haar E, Behrens AE, Fulghum JR, Lippke JA
J Biol Chem 277 37401-5 (2002)
Cited: 82 times
EuropePMC logo PMID: 12171911

Abstract

MAPK-activated protein kinase 2 (MAPKAPK2), one of several kinases directly phosphorylated and activated by p38 MAPK, plays a central role in the inflammatory response. The activated MAPKAPK2 phosphorylates its nuclear targets CREB/ATF1, serum response factor, and E2A protein E47 and its cytoplasmic targets HSP25/27, LSP-1, 5-lipoxygenase, glycogen synthase, and tyrosine hydroxylase. The crystal structure of unphosphorylated MAPKAPK2, determined at 2.8 A resolution, includes the kinase domain and the C-terminal regulatory domain. Although the protein is inactive, the kinase domain adopts an active conformation with aspartate 366 mimicking the missing phosphorylated threonine 222 in the activation loop. The C-terminal regulatory domain forms a helix-turn-helix plus a long strand. Phosphorylation of threonine 334, which is located between the kinase domain and the C-terminal regulatory domain, may serve as a switch for MAPKAPK2 nuclear import and export. Phosphorylated MAPKAPK2 masks the nuclear localization signal at its C terminus by binding to p38. It unmasks the nuclear export signal, which is part of the second C-terminal helix packed along the surface of kinase domain C-lobe, and thereby carries p38 to the cytoplasm.

Reviews - 1kwp mentioned but not cited (4)

  1. Substrate and docking interactions in serine/threonine protein kinases. Goldsmith EJ, Akella R, Min X, Zhou T, Humphreys JM. Chem Rev 107 5065-5081 (2007)
  2. Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials. Fiore M, Forli S, Manetti F. J Med Chem 59 3609-3634 (2016)
  3. Protein Kinase Targets in Breast Cancer. García-Aranda M, Redondo M. Int J Mol Sci 18 E2543 (2017)
  4. Disordered Protein Kinase Regions in Regulation of Kinase Domain Cores. Gógl G, Kornev AP, Reményi A, Taylor SS. Trends Biochem Sci 44 300-311 (2019)

Articles - 1kwp mentioned but not cited (10)

  1. The stress-responsive kinases MAPKAPK2/MAPKAPK3 activate starvation-induced autophagy through Beclin 1 phosphorylation. Wei Y, An Z, Zou Z, Sumpter R, Su M, Zang X, Sinha S, Gaestel M, Levine B. Elife 4 (2015)
  2. Sequence and structural analyses of nuclear export signals in the NESdb database. Xu D, Farmer A, Collett G, Grishin NV, Chook YM. Mol Biol Cell 23 3677-3693 (2012)
  3. Identifying protein construct variants with increased crystallization propensity--a case study. Malawski GA, Hillig RC, Monteclaro F, Eberspaecher U, Schmitz AA, Crusius K, Huber M, Egner U, Donner P, Müller-Tiemann B. Protein Sci 15 2718-2728 (2006)
  4. High-resolution crystal structure of human Mapkap kinase 3 in complex with a high affinity ligand. Cheng R, Felicetti B, Palan S, Toogood-Johnson I, Scheich C, Barker J, Whittaker M, Hesterkamp T. Protein Sci 19 168-173 (2010)
  5. Rational mutagenesis to support structure-based drug design: MAPKAP kinase 2 as a case study. Argiriadi MA, Sousa S, Banach D, Marcotte D, Xiang T, Tomlinson MJ, Demers M, Harris C, Kwak S, Hardman J, Pietras M, Quinn L, DiMauro J, Ni B, Mankovich J, Borhani DW, Talanian RV, Sadhukhan R. BMC Struct Biol 9 16 (2009)
  6. Protein aggregation profile of the human kinome. Graña-Montes R, Sant'anna de Oliveira R, Ventura S. Front Physiol 3 438 (2012)
  7. The crystal structure of the active form of the C-terminal kinase domain of mitogen- and stress-activated protein kinase 1. Malakhova M, D'Angelo I, Kim HG, Kurinov I, Bode AM, Dong Z. J Mol Biol 399 41-52 (2010)
  8. Automated identification of protein-ligand interaction features using Inductive Logic Programming: a hexose binding case study. A Santos JC, Nassif H, Page D, Muggleton SH, E Sternberg MJ. BMC Bioinformatics 13 162 (2012)
  9. A Coarse-Grained Methodology Identifies Intrinsic Mechanisms That Dissociate Interacting Protein Pairs. Abdizadeh H, Jalalypour F, Atilgan AR, Atilgan C. Front Mol Biosci 7 210 (2020)
  10. An Inductive Logic Programming Approach to Validate Hexose Binding Biochemical Knowledge. Nassif H, Al-Ali H, Khuri S, Keirouz W, Page D. Inductive Log Program 5989 149-165 (2010)


Reviews citing this publication (9)

  1. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Roux PP, Blenis J. Microbiol Mol Biol Rev 68 320-344 (2004)
  2. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Cargnello M, Roux PP. Microbiol Mol Biol Rev 75 50-83 (2011)
  3. Regulation of protein kinases; controlling activity through activation segment conformation. Nolen B, Taylor S, Ghosh G. Mol Cell 15 661-675 (2004)
  4. MAPKAP kinases - MKs - two's company, three's a crowd. Gaestel M. Nat Rev Mol Cell Biol 7 120-130 (2006)
  5. A comprehensive map of the toll-like receptor signaling network. Oda K, Kitano H. Mol Syst Biol 2 2006.0015 (2006)
  6. MAPKAPK2: the master regulator of RNA-binding proteins modulates transcript stability and tumor progression. Soni S, Anand P, Padwad YS. J Exp Clin Cancer Res 38 121 (2019)
  7. Role of the PDZ-scaffold protein NHERF1/EBP50 in cancer biology: from signaling regulation to clinical relevance. Vaquero J, Nguyen Ho-Bouldoires TH, Clapéron A, Fouassier L. Oncogene 36 3067-3079 (2017)
  8. Ste20-like kinase SLK, at the crossroads: a matter of life and death. Al-Zahrani KN, Baron KD, Sabourin LA. Cell Adh Migr 7 1-10 (2013)
  9. Novel Therapeutic Potential of Mitogen-Activated Protein Kinase Activated Protein Kinase 2 (MK2) in Chronic Airway Inflammatory Disorders. Singh RK, Najmi AK. Curr Drug Targets 20 367-379 (2019)

Articles citing this publication (59)

  1. Analysis and prediction of leucine-rich nuclear export signals. la Cour T, Kiemer L, Mølgaard A, Gupta R, Skriver K, Brunak S. Protein Eng Des Sel 17 527-536 (2004)
  2. Attributes of short linear motifs. Davey NE, Davey NE, Van Roey K, Weatheritt RJ, Toedt G, Uyar B, Altenberg B, Budd A, Diella F, Dinkel H, Gibson TJ. Mol Biosyst 8 268-281 (2012)
  3. CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Tsuyada A, Chow A, Wu J, Somlo G, Chu P, Loera S, Luu T, Li AX, Wu X, Ye W, Chen S, Zhou W, Yu Y, Wang YZ, Ren X, Li H, Scherle P, Kuroki Y, Wang SE. Cancer Res 72 2768-2779 (2012)
  4. Structural evolution of the protein kinase-like superfamily. Scheeff ED, Bourne PE. PLoS Comput Biol 1 e49 (2005)
  5. DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization. Reinhardt HC, Hasskamp P, Schmedding I, Morandell S, van Vugt MA, Wang X, Linding R, Ong SE, Weaver D, Carr SA, Yaffe MB. Mol Cell 40 34-49 (2010)
  6. Activation segment dimerization: a mechanism for kinase autophosphorylation of non-consensus sites. Pike AC, Rellos P, Niesen FH, Turnbull A, Oliver AW, Parker SA, Turk BE, Pearl LH, Knapp S. EMBO J 27 704-714 (2008)
  7. Did protein kinase regulatory mechanisms evolve through elaboration of a simple structural component? Kannan N, Neuwald AF. J Mol Biol 351 956-972 (2005)
  8. The N and C termini of the splice variants of the human mitogen-activated protein kinase-interacting kinase Mnk2 determine activity and localization. Scheper GC, Parra JL, Wilson M, Van Kollenburg B, Vertegaal AC, Han ZG, Proud CG. Mol Cell Biol 23 5692-5705 (2003)
  9. Molecular basis of MAPK-activated protein kinase 2:p38 assembly. White A, Pargellis CA, Studts JM, Werneburg BG, Farmer BT. Proc Natl Acad Sci U S A 104 6353-6358 (2007)
  10. Evidence for nucleotide receptor modulation of cross talk between MAP kinase and NF-kappa B signaling pathways in murine RAW 264.7 macrophages. Aga M, Watters JJ, Pfeiffer ZA, Wiepz GJ, Sommer JA, Bertics PJ. Am J Physiol Cell Physiol 286 C923-30 (2004)
  11. Crystal structure of the p38 alpha-MAPKAP kinase 2 heterodimer. Haar ET, Prabakhar P, Liu X, Lepre C. J Biol Chem 282 9733-9739 (2007)
  12. Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves gamma-globin activation by CREB1 and ATF-2. Sangerman J, Lee MS, Yao X, Oteng E, Hsiao CH, Li W, Zein S, Zein S, Ofori-Acquah SF, Pace BS. Blood 108 3590-3599 (2006)
  13. Endothelial LSP1 is involved in endothelial dome formation, minimizing vascular permeability changes during neutrophil transmigration in vivo. Petri B, Kaur J, Long EM, Li H, Parsons SA, Butz S, Phillipson M, Vestweber D, Patel KD, Robbins SM, Kubes P. Blood 117 942-952 (2011)
  14. Catalytically active MAP KAP kinase 2 structures in complex with staurosporine and ADP reveal differences with the autoinhibited enzyme. Underwood KW, Parris KD, Federico E, Mosyak L, Czerwinski RM, Shane T, Taylor M, Svenson K, Liu Y, Hsiao CL, Wolfrom S, Maguire M, Malakian K, Telliez JB, Lin LL, Kriz RW, Seehra J, Somers WS, Stahl ML. Structure 11 627-636 (2003)
  15. ERF nuclear shuttling, a continuous monitor of Erk activity that links it to cell cycle progression. Le Gallic L, Virgilio L, Cohen P, Biteau B, Mavrothalassitis G. Mol Cell Biol 24 1206-1218 (2004)
  16. Mitogen-activated protein kinase (MAPK) phosphatase-1 and -4 attenuate p38 MAPK during dexamethasone-induced insulin resistance in 3T3-L1 adipocytes. Bazuine M, Carlotti F, Tafrechi RS, Hoeben RC, Maassen JA. Mol Endocrinol 18 1697-1707 (2004)
  17. Prediction of leucine-rich nuclear export signal containing proteins with NESsential. Fu SC, Imai K, Horton P. Nucleic Acids Res 39 e111 (2011)
  18. High-throughput screening for soluble recombinant expressed kinases in Escherichia coli and insect cells. Chambers SP, Austen DA, Fulghum JR, Kim WM. Protein Expr Purif 36 40-47 (2004)
  19. Identification of novel phosphorylation sites in MSK1 by precursor ion scanning MS. McCoy CE, macdonald A, Morrice NA, Campbell DG, Deak M, Toth R, McIlrath J, Arthur JS. Biochem J 402 491-501 (2007)
  20. A novel role for MAPKAPK2 in morphogenesis during zebrafish development. Holloway BA, Gomez de la Torre Canny S, Ye Y, Slusarski DC, Freisinger CM, Dosch R, Chou MM, Wagner DS, Mullins MC. PLoS Genet 5 e1000413 (2009)
  21. Analyses of the effects of Rck2p mutants on Pbs2pDD-induced toxicity in Saccharomyces cerevisiae identify a MAP kinase docking motif, and unexpected functional inactivation due to acidic substitution of T379. Jiang L, Niu S, Clines KL, Burke DJ, Sturgill TW. Mol Genet Genomics 271 208-219 (2004)
  22. Phosphorylation of serine 271 on 5-lipoxygenase and its role in nuclear export. Flamand N, Luo M, Peters-Golden M, Brock TG. J Biol Chem 284 306-313 (2009)
  23. Role of MAPK kinase 6 in arthritis: distinct mechanism of action in inflammation and cytokine expression. Yoshizawa T, Hammaker D, Boyle DL, Corr M, Flavell R, Davis R, Schett G, Firestein GS. J Immunol 183 1360-1367 (2009)
  24. Design of a bioactive cell-penetrating peptide: when a transduction domain does more than transduce. Ward B, Seal BL, Brophy CM, Panitch A. J Pept Sci 15 668-674 (2009)
  25. Nuclear export inhibitors and kinase inhibitors identified using a MAPK-activated protein kinase 2 redistribution screen. Almholt DL, Loechel F, Nielsen SJ, Krog-Jensen C, Terry R, Bjørn SP, Pedersen HC, Praestegaard M, Møller S, Heide M, Pagliaro L, Mason AJ, Butcher S, Dahl SW. Assay Drug Dev Technol 2 7-20 (2004)
  26. TRPV4 Protects the Lung from Bacterial Pneumonia via MAPK Molecular Pathway Switching. Scheraga RG, Abraham S, Grove LM, Southern BD, Crish JF, Perelas A, McDonald C, Asosingh K, Hasday JD, Olman MA. J Immunol 204 1310-1321 (2020)
  27. Activation of the extracellular signal-regulated kinase by complement C5b-9. Cybulsky AV, Takano T, Papillon J, Bijian K, Guillemette J. Am J Physiol Renal Physiol 289 F593-603 (2005)
  28. Arsenic down-regulates the expression of Camk4, an important gene related to cerebellar LTD in mice. Wang Y, Li S, Piao F, Hong Y, Liu P, Zhao Y. Neurotoxicol Teratol 31 318-322 (2009)
  29. RND2 attenuates apoptosis and autophagy in glioblastoma cells by targeting the p38 MAPK signalling pathway. Xu Y, Sun Q, Yuan F, Dong H, Zhang H, Geng R, Qi Y, Xiong X, Chen Q, Liu B. J Exp Clin Cancer Res 39 174 (2020)
  30. Modulation of p38 kinase by DUSP4 is important in regulating cardiovascular function under oxidative stress. Barajas-Espinosa A, Basye A, Angelos MG, Chen CA. Free Radic Biol Med 89 170-181 (2015)
  31. Structural assembly of the signaling competent ERK2-RSK1 heterodimeric protein kinase complex. Alexa A, Gógl G, Glatz G, Garai Á, Zeke A, Varga J, Dudás E, Jeszenői N, Bodor A, Hetényi C, Reményi A. Proc Natl Acad Sci U S A 112 2711-2716 (2015)
  32. Structural basis for a high affinity inhibitor bound to protein kinase MK2. Hillig RC, Eberspaecher U, Monteclaro F, Huber M, Nguyen D, Mengel A, Muller-Tiemann B, Egner U. J Mol Biol 369 735-745 (2007)
  33. Understanding the molecular basis of MK2-p38α signaling complex assembly: insights into protein-protein interaction by molecular dynamics and free energy studies. Yang Y, Liu H, Yao X. Mol Biosyst 8 2106-2118 (2012)
  34. DNA repair protein biomarkers associated with time to recurrence in triple-negative breast cancer. Alexander BM, Sprott K, Farrow DA, Wang X, D'Andrea AD, Schnitt SJ, Collins LC, Weaver DT, Garber JE. Clin Cancer Res 16 5796-5804 (2010)
  35. Adapting glycolysis to cancer cell proliferation: the MAPK pathway focuses on PFKFB3. Bolaños JP. Biochem J 452 e7-9 (2013)
  36. Phosphorylation and function of the kaposin B direct repeats of Kaposi's sarcoma-associated herpesvirus. McCormick C, Ganem D. J Virol 80 6165-6170 (2006)
  37. Discovery and Hit-to-Lead Optimization of Non-ATP Competitive MK2 (MAPKAPK2) Inhibitors. Huang X, Shipps GW, Cheng CC, Spacciapoli P, Zhang X, McCoy MA, Wyss DF, Yang X, Achab A, Soucy K, Montavon DK, Murphy DM, Whitehurst CE. ACS Med Chem Lett 2 632-637 (2011)
  38. High-content screening analysis of the p38 pathway: profiling of structurally related p38alpha kinase inhibitors using cell-based assays. Ross S, Chen T, Yu V, Tudor Y, Zhang D, Liu L, Tamayo N, Dominguez C, Powers D. Assay Drug Dev Technol 4 397-409 (2006)
  39. Mitogen-activated protein kinase-activated protein kinase 2 (MK2) in skeletal muscle atrophy and hypertrophy. Norrby M, Tågerud S. J Cell Physiol 223 194-201 (2010)
  40. MYC transcription activation mediated by OCT4 as a mechanism of resistance to 13-cisRA-mediated differentiation in neuroblastoma. Wei SJ, Nguyen TH, Yang IH, Mook DG, Makena MR, Verlekar D, Hindle A, Martinez GM, Yang S, Shimada H, Reynolds CP, Kang MH. Cell Death Dis 11 368 (2020)
  41. Effect of construct design on MAPKAP kinase-2 activity, thermodynamic stability and ligand-binding affinity. Kervinen J, Ma H, Bayoumy S, Schubert C, Milligan C, Lewandowski F, Moriarty K, Desjarlais RL, Ramachandren K, Wang H, Harris CA, Grasberger B, Todd M, Springer BA, Deckman I. Arch Biochem Biophys 449 47-56 (2006)
  42. HISP: a hybrid intelligent approach for identifying directed signaling pathways. Zhao XM, Li S. J Mol Cell Biol 9 453-462 (2017)
  43. Structural and functional basis for p38-MK2-activated Rsk signaling in toll-like receptor-stimulated dendritic cells. Zaru R, Edgar AJ, Hanauer A, Watts C. Mol Cell Biol 35 132-140 (2015)
  44. Structural basis for the autoinhibition of the C-terminal kinase domain of human RSK1. Li D, Fu TM, Nan J, Liu C, Li LF, Su XD. Acta Crystallogr D Biol Crystallogr 68 680-685 (2012)
  45. A 'pure' chemoattractant formylpeptide analogue triggers a specific signalling pathway in human neutrophil chemotaxis. Spisani S, Falzarano S, Traniello S, Nalli M, Selvatici R. FEBS J 272 883-891 (2005)
  46. Immune prevention of mammary carcinogenesis in HER-2/neu transgenic mice: a microarray scenario. Astolfi A, Rolla S, Nanni P, Quaglino E, De Giovanni C, Iezzi M, Musiani P, Forni G, Lollini PL, Cavallo F, Calogero RA. Cancer Immunol Immunother 54 599-610 (2005)
  47. 2,4-Diaminopyrimidine MK2 inhibitors. Part I: Observation of an unexpected inhibitor binding mode. Argiriadi MA, Ericsson AM, Harris CM, Banach DL, Borhani DW, Calderwood DJ, Demers MD, Dimauro J, Dixon RW, Hardman J, Kwak S, Li B, Mankovich JA, Marcotte D, Mullen KD, Ni B, Pietras M, Sadhukhan R, Sousa S, Tomlinson MJ, Wang L, Xiang T, Talanian RV. Bioorg Med Chem Lett 20 330-333 (2010)
  48. Cellular trafficking of the IL-1RI-associated kinase-1 requires intact kinase activity. Böl GF, Jurrmann N, Brigelius-Flohé R. Biochem Biophys Res Commun 332 279-287 (2005)
  49. Cytokine regulation by MAPK activated kinase 2 in keratinocytes exposed to sulfur mustard. Yego EC, Dillman JF. Toxicol In Vitro 27 2067-2075 (2013)
  50. Staurosporine-based binding assay for testing the affinity of compounds to protein kinases. Iyer GH, Taslimi P, Pazhanisamy S. Anal Biochem 373 197-206 (2008)
  51. p38 mitogen-activated protein kinase and mitogen-activated protein kinase-activated protein kinase 2 (MK2) signaling in atrophic and hypertrophic denervated mouse skeletal muscle. Evertsson K, Fjällström AK, Norrby M, Tågerud S. J Mol Signal 9 2 (2014)
  52. MAP Kinase-Mediated Activation of RSK1 and MK2 Substrate Kinases. Sok P, Gógl G, Kumar GS, Alexa A, Singh N, Kirsch K, Sebő A, Drahos L, Gáspári Z, Peti W, Reményi A. Structure 28 1101-1113.e5 (2020)
  53. Mitogen-activated protein kinase-activated protein kinase-2 (MK2) and its role in cell survival, inflammatory signaling, and migration in promoting cancer. Morgan D, Berggren KL, Spiess CD, Smith HM, Tejwani A, Weir SJ, Lominska CE, Thomas SM, Gan GN. Mol Carcinog 61 173-199 (2022)
  54. A p38 substrate-specific MK2-EGFP translocation assay for identification and validation of new p38 inhibitors in living cells: a comprising alternative for acquisition of cellular p38 inhibition data. Anton R, Bauer SM, Keck PR, Laufer S, Rothbauer U. PLoS One 9 e95641 (2014)
  55. Comment Activating MAP KAP kinase 2. ter Haar E. Structure 11 611-612 (2003)
  56. Assessment of the putative binding conformation of a pyrazolopyridine class of inhibitors of MAPKAPK2 using computational studies. Miglani R, Cliffe IA, Voleti SR. Eur J Med Chem 45 98-105 (2010)
  57. Structural analysis of an MK2-inhibitor complex: insight into the regulation of the secondary structure of the Gly-rich loop by TEI-I01800. Fujino A, Fukushima K, Namiki N, Kosugi T, Takimoto-Kamimura M. Acta Crystallogr D Biol Crystallogr 66 80-87 (2010)
  58. Time-resolved limited proteolysis of mitogen-activated protein kinase-activated protein kinase-2 determined by LC/MS only. Tao L, Kiefer SE, Xie D, Bryson JW, Hefta SA, Doyle ML. J Am Soc Mass Spectrom 19 841-854 (2008)
  59. Activation and inhibition of the C-terminal kinase domain of p90 ribosomal S6 kinases. Fruergaard MU, Nielsen CJF, Kjeldsen CR, Iversen L, Andersen JL, Nissen P. Life Sci Alliance 6 e202201425 (2023)


Quick links