What goes up must come down: molecular basis of MAPKAP kinase 2/3-dependent regulation of the inflammatory response and its inhibition

References

Ananieva, O., Darragh, J., Johansen, C., Carr, J.M., McIlrath, J., Park, J.M., Wingate, A., Monk, C.E., Toth, R., Santos, S.G., et al. (2008). The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling. Nat Immunol 9, 1028–1036.10.1038/ni.1644Search in Google Scholar PubMed

Anderson, D.R., Meyers, M.J., Vernier, W.F., Mahoney, M.W., Kurumbail, R.G., Caspers, N., Poda, G.I., Schindler, J.F., Reitz, D.B., and Mourey, R.J. (2007). Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). J Med Chem 50, 2647–2654.10.1021/jm0611004Search in Google Scholar PubMed

Anderson, P. (2008). Post-transcriptional control of cytokine production. Nat Immunol 9, 353–359.10.1038/ni1584Search in Google Scholar PubMed

Anderson, D.R., Meyers, M.J., Kurumbail, R.G., Caspers, N., Poda, G.I., Long, S.A., Pierce, B.S., Mahoney, M.W., and Mourey, R.J. (2009a). Benzothiophene inhibitors of MK2. Part 1: structure-activity relationships, assessments of selectivity and cellular potency. Bioorg Med Chem Lett 19, 4878–4881.10.1016/j.bmcl.2009.02.015Search in Google Scholar PubMed

Anderson, D.R., Meyers, M.J., Kurumbail, R.G., Caspers, N., Poda, G.I., Long, S.A., Pierce, B.S., Mahoney, M.W., Mourey, R.J., and Parikh, M.D. (2009b). Benzothiophene inhibitors of MK2. Part 2: improvements in kinase selectivity and cell potency. Bioorg Med Chem Lett 19, 4882–4884.10.1016/j.bmcl.2009.02.017Search in Google Scholar PubMed

Argiriadi, M.A., Ericsson, A.M., Harris, C.M., Banach, D.L., Borhani, D.W., Calderwood, D.J., Demers, M.D., Dimauro, J., Dixon, R.W., Hardman, J., et al. (2010). 2,4-Diaminopyrimidine MK2 inhibitors. Part I: Observation of an unexpected inhibitor binding mode. Bioorg Med Chem Lett 20, 330–333.10.1016/j.bmcl.2009.10.102Search in Google Scholar PubMed

Barf, T., Kaptein, A., de Wilde, S., van der Heijden, R., van Someren, R., Demont, D., Schultz-Fademrecht, C., Versteegh, J., van Zeeland, M., Seegers, N., et al. (2011). Structure-based lead identification of ATP-competitive MK2 inhibitors. Bioorg Med Chem Lett 21, 3818–3822.10.1016/j.bmcl.2011.04.018Search in Google Scholar PubMed

Bendall, S.C., Simonds, E.F., Qiu, P., Amir, E.-A.D., Krutzik, P.O., Finck, R., Bruggner, R.V., Melamed, R., Trejo, A., Ornatsky, O.I., et al. (2011). Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. Science 332, 687–696.10.1126/science.1198704Search in Google Scholar PubMed PubMed Central

Bobo, L.D., El Feghaly, R.E., Chen, Y.-S., Dubberke, E.R., Han, Z., Baker, A., Li, J., Burnham, C.-A., and Haslam, D.B. (2013). MAPK-activated protein kinase 2 contributes to Clostridium difficile-associated inflammation. Infect Immun 81, 713–722.10.1128/IAI.00186-12Search in Google Scholar PubMed PubMed Central

Bode, J.G., Ehlting, C., and Häussinger, D. (2012). The macrophage response towards LPS and its control through the p38(MAPK)-STAT3 axis. Cell Signal 24, 1185–1194.10.1016/j.cellsig.2012.01.018Search in Google Scholar PubMed

Bollig, F., Winzen, R., Gaestel, M., Kostka, S., Resch, K., and Holtmann, H. (2003). Affinity purification of ARE-binding proteins identifies polyA-binding protein 1 as a potential substrate in MK2-induced mRNA stabilization. Biochem Biophys Res Commun 301, 665–670.10.1016/S0006-291X(03)00015-9Search in Google Scholar

Braun, T., Lepper, J., Heiland, G.R., Hofstetter, W., Siegrist, M., Lezuo, P., Gaestel, M., Rumpler, M., Thaler, R., Klaushofer, K., et al. (2013). Mitogen-activated protein kinase 2 regulates physiological and pathological bone turnover. J Bone Miner Res 28, 936–947.10.1002/jbmr.1816Search in Google Scholar

Brugnano, J.L., Chan, B.K., Seal, B.L., and Panitch, A. (2011). Cell-penetrating peptides can confer biological function: regulation of inflammatory cytokines in human monocytes by MK2 inhibitor peptides. J Control Release 155, 128–133.10.1016/j.jconrel.2011.05.007Search in Google Scholar

Carballo, E. (1998). Feedback inhibition of macrophage tumor necrosis factor-production by tristetraprolin. Science 281, 1001–1005.10.1126/science.281.5379.1001Search in Google Scholar

Cheng, R., Felicetti, B., Palan, S., Toogood-Johnson, I., Scheich, C., Barker, J., Whittaker, M., and Hesterkamp, T. (2010). High-resolution crystal structure of human Mapkap kinase 3 in complex with a high affinity ligand. Protein Sci 19, 168–173.Search in Google Scholar

Chrestensen, C.A., Schroeder, M.J., Shabanowitz, J., Hunt, D.F., Pelo, J.W., Worthington, M.T. and Sturgill, T.W. (2004). MAPKAP kinase 2 phosphorylates tristetraprolin on in vivo sites including Ser178, a site required for 14-3-3 binding. J Biol Chem 279, 10176–10184.10.1074/jbc.M310486200Search in Google Scholar

Clement, S.L., Scheckel, C., Stoecklin, G., and Lykke-Andersen, J. (2011). Phosphorylation of tristetraprolin by MK2 impairs AU-rich element mRNA decay by preventing deadenylase recruitment. Mol Cell Biol 31, 256–266.10.1128/MCB.00717-10Search in Google Scholar

Clifton, A.D., Young, P.R., and Cohen, P. (1996). A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAP kinase-3 and their activation by cytokines and cellular stress. FEBS Lett 392, 209–214.10.1016/0014-5793(96)00816-2Search in Google Scholar

Cohen, P. (2009). Targeting protein kinases for the development of anti-inflammatory drugs. Curr Opin Cell Biol 21, 317–324.10.1016/j.ceb.2009.01.015Search in Google Scholar PubMed

Coller, J. and Parker, R. (2005). General translational repression by activators of mRNA decapping. Cell 122, 875–886.10.1016/j.cell.2005.07.012Search in Google Scholar PubMed PubMed Central

Corcoran, J.A., Khaperskyy, D.A., Johnston, B.P., King, C.A., Cyr, D.P., Olsthoorn, A.V., and McCormick, C. (2012). Kaposi’s sarcoma-associated herpes virus G-protein-coupled receptor prevents AU-rich-element-mediated mRNA decay. J Virol 86, 8859–8871.10.1128/JVI.00597-12Search in Google Scholar PubMed PubMed Central

Davidson, W., Frego, L., Peet, G.W., Kroe, R.R., Labadia, M.E., Lukas, S.M., Snow, R.J., Jakes, S., Grygon, C.A., Pargellis, C., et al. (2004). Discovery and characterization of a substrate selective p38alpha inhibitor. Biochemistry 43, 11658–11671.10.1021/bi0495073Search in Google Scholar

Dominguez, C., Powers, D.A., and Tamayo, N. (2005). p38 MAP kinase inhibitors: many are made, but few are chosen. Curr Opin Drug Discov Devel 8, 421–430.Search in Google Scholar

Dulos, J., Wijnands, F.P.G., van den Hurk-van Alebeek, J.A.J., van Vugt, M.J.H., Rullmann, J.A.C., Schot, J.-J.G., de Groot, M.W.G.D.M., Wagenaars, J.L., van Ravestein-van Os, R., Smets, R.L., et al. (2013). p38 inhibition and not MK2 inhibition enhances the secretion of chemokines from TNF-α activated rheumatoid arthritis fibroblast-like synoviocytes. Clin Exp Rheumatol Apr 3. [Epub ahead of print]Search in Google Scholar

Dumitru, C.D., Ceci, J.D., Tsatsanis, C., Kontoyiannis, D., Stamatakis, K., Lin, J.H., Patriotis, C., Jenkins, N.A., Copeland, N.G., Kollias, G., et al. (2000). TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 103, 1071–1083.10.1016/S0092-8674(00)00210-5Search in Google Scholar

Ebrahimian, T., Li, M.W., Lemarié, C.A., Simeone, S.M.C., Pagano, P.J., Gaestel, M., Paradis, P., Wassmann, S., and Schiffrin, E.L. (2011). Mitogen-activated protein kinase-activated protein kinase 2 in angiotensin II-induced inflammation and hypertension: regulation of oxidative stress. Hypertension 57, 245–254.10.1161/HYPERTENSIONAHA.110.159889Search in Google Scholar PubMed PubMed Central

Ehlting, C., Lai, W.S., Schaper, F., Brenndörfer, E.D., Matthes, R.-J., Heinrich, P.C., Ludwig, S., Blackshear, P.J., Gaestel, M., Häussinger, D., et al. (2007). Regulation of suppressor of cytokine signaling 3 (SOCS3) mRNA stability by TNF-α involves activation of the MKK6/p38MAPK/MK2 cascade. J Immunol 178, 2813–2826.10.4049/jimmunol.178.5.2813Search in Google Scholar PubMed

Ehlting, C., Ronkina, N., Böhmer, O., Albrecht, U., Bode, K.A., Lang, K.S., Kotlyarov, A., Radzioch, D., Gaestel, M., Häussinger, D., et al. (2011). Distinct functions of the mitogen-activated protein kinase-activated protein (MAPKAP) kinases MK2 and MK3: MK2 mediates lipopolysaccharide-induced signal transducers and activators of transcription 3 (STAT3) activation by preventing negative regulatory effects of MK3. J Biol Chem 286, 24113–24124.10.1074/jbc.M111.235275Search in Google Scholar PubMed PubMed Central

Frank, F., Rouya, C., Siddiqui, N., Lai, W.S., Karetnikov, A., Blackshear, P.J., Fabian, M.R., Nagar, B., and Sonenberg, N. (2013). Structural basis for the recruitment of the human CCR4–NOT deadenylase complex by tristetraprolin. Nat Struct Mol Biol 20, 735–739.10.1038/nsmb.2572Search in Google Scholar PubMed PubMed Central

Fujino, A., Fukushima, K., Namiki, N., Kosugi, T., and Takimoto-Kamimura, M. (2010). Structural analysis of an MK2-inhibitor complex: insight into the regulation of the secondary structure of the Gly-rich loop by TEI-I01800. Acta Crystallogr D Biol Crystallogr 66, 80–87.10.1107/S0907444909046411Search in Google Scholar PubMed

Funding, A.T., Johansen, C., Gaestel, M., Bibby, B.M., Lilleholt, L.L., Kragballe, K., and Iversen, L. (2009). Reduced oxazolone-induced skin inflammation in MAPKAP kinase 2 knockout mice. J Invest Dermatol 129, 891–898.10.1038/jid.2008.322Search in Google Scholar PubMed

Fyhrquist, N., Matikainen, S., and Lauerma, A. (2010). MK2 signaling: lessons on tissue specificity in modulation of inflammation. J Invest Dermatol 130, 342–344.10.1038/jid.2009.372Search in Google Scholar PubMed

Gaestel, M. (2006). MAPKAP kinases – MKs – two’s company, three’s a crowd. Nat Rev Mol Cell Biol 7, 120–130.10.1038/nrm1834Search in Google Scholar PubMed

Gaestel, M., Kotlyarov, A., and Kracht, M. (2009). Targeting innate immunity protein kinase signalling in inflammation. Nat Rev Drug Discov 8, 480–499.10.1038/nrd2829Search in Google Scholar

Gais, P., Tiedje, C., Altmayr, F., Gaestel, M., Weighardt, H., and Holzmann, B. (2010). TRIF signaling stimulates translation of TNF-α mRNA via prolonged activation of MK2. J Immunol 184, 5842–5848.10.4049/jimmunol.0902456Search in Google Scholar

Genovese, M.C., Cohen, S.B., Wofsy, D., Weinblatt, M.E., Firestein, G.S., Brahn, E., Strand, V., Baker, D.G., and Tong, S.E. (2011). A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase inhibitor, in patients with active rheumatoid arthritis. J Rheumatol 38, 846–854.10.3899/jrheum.100602Search in Google Scholar

Guess, A.J., Ayoob, R., Chanley, M., Manley, J., Cajaiba, M.M., Agrawal, S., Pengal, R., Pyle, A.L., Becknell, B., Kopp, J.B., et al. (2013). Crucial roles of the protein kinases MK2 and MK3 in a mouse model of glomerulonephritis. PLoS One 8, e54239.10.1371/journal.pone.0054239Search in Google Scholar

Han, J., Lee, J.D., Bibbs, L., and Ulevitch, R.J. (1994). A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265, 808–811.10.1126/science.7914033Search in Google Scholar

Hannigan, M.O., Zhan, L., Ai, Y., Kotlyarov, A., Gaestel, M., and Huang, C.K. (2001). Abnormal migration phenotype of mitogen-activated protein kinase-activated protein kinase 2^-/- neutrophils in Zigmond chambers containing formyl-methionyl-leucyl-phenylalanine gradients. J Immunol 167, 3953–3961.10.4049/jimmunol.167.7.3953Search in Google Scholar

Harris, C.M., Ericsson, A.M., Argiriadi, M.A., Barberis, C., Borhani, D.W., Burchat, A., Calderwood, D.J., Cunha, G.A., Dixon, R.W., Frank, K.E., et al. (2010). 2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization. Bioorg Med Chem Lett 20, 334–337.10.1016/j.bmcl.2009.10.103Search in Google Scholar

Hayess, K. and Benndorf, R. (1997). Effect of protein kinase inhibitors on activity of mammalian small heat-shock protein (HSP25) kinase. Biochem Pharmacol 53, 1239–1247.10.1016/S0006-2952(96)00877-5Search in Google Scholar

Hegen, M., Gaestel, M., Nickerson-Nutter, C.L., Lin, L.-L., and Telliez, J.-B. (2006). MAPKAP kinase 2-deficient mice are resistant to collagen-induced arthritis. J Immunol 177, 1913–1917.10.4049/jimmunol.177.3.1913Search in Google Scholar PubMed

Hillig, R.C., Eberspaecher, U., Monteclaro, F., Huber, M., Nguyen, D., Mengel, A., Muller-Tiemann, B., and Egner, U. (2007). Structural basis for a high affinity inhibitor bound to protein kinase MK2. J Mol Biol 369, 735–745.10.1016/j.jmb.2007.03.004Search in Google Scholar PubMed

Hitti, E., Iakovleva, T., Brook, M., Deppenmeier, S., Gruber, A.D., Radzioch, D., Clark, A.R., Blackshear, P.J., Kotlyarov, A., and Gaestel, M. (2006). Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element. Mol Cell Biol 26, 2399–2407.10.1128/MCB.26.6.2399-2407.2006Search in Google Scholar

Huang, X., Zhu, X., Chen, X., Zhou, W., Xiao, D., Degrado, S., Aslanian, R., Fossetta, J., Lundell, D., Tian, F., et al. (2012). A three-step protocol for lead optimization: quick identification of key conformational features and functional groups in the SAR studies of non-ATP competitive MK2 (MAPKAPK2) inhibitors. Bioorg Med Chem Lett 22, 65–70.10.1016/j.bmcl.2011.11.074Search in Google Scholar

Johansen, C., Vestergaard, C., Kragballe, K., Kollias, G., Gaestel, M., and Iversen, L. (2009). MK2 regulates the early stages of skin tumor promotion. Carcinogenesis 30, 2100–2108.10.1093/carcin/bgp238Search in Google Scholar

Kahle, N.A., Brenner-Weiss, G., Overhage, J., Obst, U., and Hänsch, G.M. (2013). Bacterial quorum sensing molecule induces chemotaxis of human neutrophils via induction of p38 and leukocyte specific protein 1 (LSP1). Immunobiology 218, 145–151.10.1016/j.imbio.2012.02.004Search in Google Scholar

Kawai, T., Lal, A., Yang, X., Galban, S., Mazan-Mamczarz, K., and Gorospe, M. (2006). Translational control of cytochrome c by RNA-binding proteins TIA-1 and HuR. Mol Cell Biol 26, 3295–3307.10.1128/MCB.26.8.3295-3307.2006Search in Google Scholar

Kosugi, T., Mitchell, D.R., Fujino, A., Imai, M., Kambe, M., Kobayashi, S., Makino, H., Matsueda, Y., Oue, Y., Komatsu, K., et al. (2012). Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) as an anti-inflammatory target: discovery and in vivo activity of selective pyrazolo[1,5-a]pyrimidine inhibitors using a focused library and structure-based optimisation approach. J Med Chem 55, 6700–6715.10.1021/jm300411kSearch in Google Scholar

Kotlyarov, A., Neininger, A., Schubert, C., Eckert, R., Birchmeier, C., Volk, H.D., and Gaestel, M. (1999). MAPKAP kinase 2 is essential for LPS-induced TNF-α biosynthesis. Nat Cell Biol 1, 94–97.10.1038/10061Search in Google Scholar

Kriegler, M., Perez, C., DeFay, K., Albert, I., and Lu, S.D. (1988). A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell 53, 45–53.10.1016/0092-8674(88)90486-2Search in Google Scholar

Kullmann, M., Göpfert, U., Siewe, B., and Hengst, L. (2002). ELAV/Hu proteins inhibit p27 translation via an IRES element in the p27 5′UTR. Genes Dev 16, 3087–3099.10.1101/gad.248902Search in Google Scholar PubMed PubMed Central

Lee, J.C., Laydon, J.T., McDonnell, P.C., Gallagher, T.F., Kumar, S., Green, D., McNulty, D., Blumenthal, M.J., Heys, J.R., and Landvatter, S.W. (1994). A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739–746.10.1038/372739a0Search in Google Scholar PubMed

Lehner, M.D., Schwoebel, F., Kotlyarov, A., Leist, M., Gaestel, M., and Hartung, T. (2002). Mitogen-activated protein kinase-activated protein kinase 2-deficient mice show increased susceptibility to Listeria monocytogenes infection. J Immunol 168, 4667–4673.10.4049/jimmunol.168.9.4667Search in Google Scholar PubMed

Leppek, K., Schott, J., Reitter, S., Poetz, F., Hammond, M.C., and Stoecklin, G. (2013). Roquin Promotes constitutive mRNA Decay via a conserved class of stem-loop recognition motifs. Cell 153, 869–881.10.1016/j.cell.2013.04.016Search in Google Scholar PubMed

Li, Q., Yu, H., Zinna, R., Martin, K., Herbert, B., Liu, A., Rossa, C., and Kirkwood, K.L. (2011). Silencing mitogen-activated protein kinase-activated protein kinase-2 arrests inflammatory bone loss. J Pharmacol Exp Ther 336, 633–642.10.1124/jpet.110.172395Search in Google Scholar PubMed PubMed Central

Li, Y.Y., Yuece, B., Cao, H.M., Lin, H.X., Lv, S., Chen, J.C., Ochs, S., Sibaev, A., Deindl, E., Schaefer, C., et al. (2013). Inhibition of p38/Mk2 signaling pathway improves the anti-inflammatory effect of WIN55 on mouse experimental colitis. Lab Invest 93, 322–333.10.1038/labinvest.2012.177Search in Google Scholar PubMed

Liu, T., Milia, E., Warburton, R.R., Hill, N.S., Gaestel, M., and Kayyali, U.S. (2012). Anthrax lethal toxin disrupts the endothelial permeability barrier through blocking p38 signaling. J Cell Physiol 227, 1438–1445.10.1002/jcp.22859Search in Google Scholar PubMed PubMed Central

Lovering, F., Kirincich, S., Wang, W., Combs, K., Resnick, L., Sabalski, J.E., Butera, J., Liu, J., Parris, K., and Telliez, J.-B. (2009). Identification and SAR of squarate inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2). Bioorg Med Chem 17, 3342–3351.10.1016/j.bmc.2009.03.041Search in Google Scholar PubMed

Marchese, F.P., Aubareda, A., Tudor, C., Saklatvala, J., Clark, A.R., and Dean, J.L.E. (2010). MAPKAP kinase 2 blocks tristetraprolin-directed mRNA decay by inhibiting CAF1 deadenylase recruitment. J Biol Chem 285, 27590–27600.10.1074/jbc.M110.136473Search in Google Scholar PubMed PubMed Central

McCormick, C., and Ganem, D. (2005). The kaposin B protein of KSHV activates the p38/MK2 pathway and stabilizes cytokine mRNAs. Science 307, 739–741.10.1126/science.1105779Search in Google Scholar PubMed

Moens, U., Kostenko, S., and Sveinbjørnsson, B. (2013). The role of mitogen-activated protein kinase-activated protein kinases (MAPKAPKs) in inflammation. Genes 4, 101–133.10.3390/genes4020101Search in Google Scholar PubMed PubMed Central

Moriguchi, T., Kuroyanagi, N., Yamaguchi, K., Gotoh, Y., Irie, K., Kano, T., Shirakabe, K., Muro, Y., Shibuya, H., Matsumoto, K., et al. (1996). A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. J Biol Chem 271, 13675–13679.10.1074/jbc.271.23.13675Search in Google Scholar PubMed

Mourey, R.J., Burnette, B.L., Brustkern, S.J., Daniels, J.S., Hirsch, J.L., Hood, W.F., Meyers, M.J., Mnich, S.J., Pierce, B.S., Saabye, M.J., et al. (2010). A benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor α production and has oral anti-inflammatory efficacy in acute and chronic models of inflammation. J Pharmacol Exp Ther 333, 797–807.10.1124/jpet.110.166173Search in Google Scholar PubMed

Neininger, A., Kontoyiannis, D., Kotlyarov, A., Winzen, R., Eckert, R., Volk, H.-D., Holtmann, H., Kollias, G., and Gaestel, M. (2002). MK2 targets AU-rich elements and regulates biosynthesis of tumor necrosis factor and interleukin-6 independently at different post-transcriptional levels. J Biol Chem 277, 3065–3068.10.1074/jbc.C100685200Search in Google Scholar PubMed

O’Dea, K.P., Dokpesi, J.O., Tatham, K.C., Wilson, M.R., and Takata, M. (2011). Regulation of monocyte subset proinflammatory responses within the lung microvasculature by the p38 MAPK/MK2 pathway. Am J Physiol Lung Cell Mol Physiol 301, L812–L821.10.1152/ajplung.00092.2011Search in Google Scholar PubMed PubMed Central

Osman, F., Jarrous, N., Ben-Asouli, Y., and Kaempfer, R. (1999). A cis-acting element in the 3′-untranslated region of human TNF-α mRNA renders splicing dependent on the activation of protein kinase PKR. Genes Dev 13, 3280–3293.10.1101/gad.13.24.3280Search in Google Scholar PubMed PubMed Central

Oubrie, A., Kaptein, A., de Zwart, E., Hoogenboom, N., Goorden, R., van de Kar, B., van Hoek, M., de Kimpe, V., van der Heijden, R., Borsboom, J., et al. (2011). Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series. Bioorg Med Chem Lett 22, 613–618.10.1016/j.bmcl.2011.10.071Search in Google Scholar PubMed

Pfeiffer, J.R. and Brooks, S.A. (2012). Cullin 4B is recruited to tristetraprolin-containing messenger ribonucleoproteins and regulates TNF-α mRNA polysome loading. J Immunol 188, 1828–1839.10.4049/jimmunol.1102837Search in Google Scholar PubMed

Pratama, A., Ramiscal, R.R., Silva, D.G., Das, S.K., Athanasopoulos, V., Fitch, J., Botelho, N.K., Chang, P.-P., Hu, X., Hogan, J.J., et al. (2013). Roquin-2 shares functions with its paralog roquin-1 in the repression of mRNAs controlling T follicular helper cells and systemic inflammation. Immunity 38, 669–680.10.1016/j.immuni.2013.01.011Search in Google Scholar PubMed

Prickaerts, P., Niessen, H.E., Mouchel-Vielh, E., Dahlmans, V.E., van den Akker, G.G., Geijselaers, C., Adriaens, M.E., Spaapen, F., Takihara, Y., Rapp, U.R., et al. (2012). MK3 controls Polycomb target gene expression via negative feedback on ERK. Epigenetics Chromatin 5, 1–13.10.1186/1756-8935-5-12Search in Google Scholar PubMed PubMed Central

Qi, M.-Y., Wang, Z.-Z., Zhang, Z., Shao, Q., Zeng, A., Li, X.-Q., Li, W.-Q., Wang, C., Tian, F.-J., Li, Q., et al. (2011). AU-rich element-dependent translation repression requires the cooperation of tristetraprolin and RCK/P54. Mol Cell Biol 32, 913–928.10.1128/MCB.05340-11Search in Google Scholar PubMed PubMed Central

Qiu, P., Simonds, E.F., Bendall, S.C., Gibbs, K.D., Bruggner, R.V., Linderman, M.D., Sachs, K., Nolan, G.P., and Plevritis, S.K. (2011). Extracting a cellular hierarchy from high-dimensional cytometry data with SPADE. Nat Biotechnol 29, 886–891.10.1038/nbt.1991Search in Google Scholar PubMed PubMed Central

Radtke, S., Wüller, S., Yang, X.-P., Lippok, B.E., Mütze, B., Mais, C., de Leur, H.S.-V., Bode, J.G., Gaestel, M., Heinrich, P.C., et al. (2010a). Cross-regulation of cytokine signalling: pro-inflammatory cytokines restrict IL-6 signalling through receptor internalisation and degradation. J Cell Sci 123, 947–959.10.1242/jcs.065326Search in Google Scholar PubMed

Radtke, S., Wüller, S., Yang, X.-P., Lippok, B.E., Mütze, B., Mais, C., de Leur, H.S.-V., Bode, J.G., Gaestel, M., Heinrich, P.C., et al. (2010b). Cross-regulation of cytokine signalling: pro-inflammatory cytokines restrict IL-6 signalling through receptor internalisation and degradation. J Cell Sci 123, 947–959.10.1242/jcs.065326Search in Google Scholar

Rajaram, M.V.S., Ni, B., Morris, J.D., Brooks, M.N., Carlson, T.K., Bakthavachalu, B., Schoenberg, D.R., Torrelles, J.B., and Schlesinger, L.S. (2011). Mycobacterium tuberculosis lipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b. Proc Natl Acad Sci USA 108, 17408–17413.10.1073/pnas.1112660108Search in Google Scholar PubMed PubMed Central

Risco, A., Del Fresno, C., Mambol, A., Alsina-Beauchamp, D., Mackenzie, K.F., Yang, H.-T., Barber, D.F., Morcelle, C., Arthur, J.S.C., Ley, S.C., et al. (2012). p38γ and p38δ kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation. Proc Natl Acad Sci USA 109, 11200–11205.10.1073/pnas.1207290109Search in Google Scholar PubMed PubMed Central

Ronkina, N., Kotlyarov, A., Dittrich-Breiholz, O., Kracht, M., Hitti, E., Milarski, K., Askew, R., Marusic, S., Lin, L.-L., Gaestel, M., et al. (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, 170–181.10.1128/MCB.01456-06Search in Google Scholar PubMed PubMed Central

Ronkina, N., Menon, M.B., Schwermann, J., Arthur, J.S.C., Legault, H., Telliez, J.-B., Kayyali, U.S., Nebreda, A.R., Kotlyarov, A., and Gaestel, M. (2011). Stress induced gene expression: a direct role for MAPKAP kinases in transcriptional activation of immediate early genes. Nucleic Acids Res 39, 2503–2518.10.1093/nar/gkq1178Search in Google Scholar PubMed PubMed Central

Rousseau, S., Papoutsopoulou, M., Symons, A., Cook, D., Lucocq, J.M., Prescott, A.R., O’Garra, A., Ley, S.C., and Cohen, P. (2008). TPL2-mediated activation of ERK1 and ERK2 regulates the processing of pre-TNFα in LPS-stimulated macrophages. J Cell Sci 121, 149–154.10.1242/jcs.018671Search in Google Scholar PubMed

Rousseau, S., Peggie, M., Campbell, D.G., Nebreda, A.R., and Cohen, P. (2005). Nogo-B is a new physiological substrate for MAPKAP-K2. Biochem J 391, 433–440.10.1042/BJ20050935Search in Google Scholar PubMed PubMed Central

Saenz, J.B., Li, J., and Haslam, D.B. (2010). The MAP kinase-activated protein kinase 2 (MK2) contributes to the Shiga toxin-induced inflammatory response. Cell Microbiol 12, 516–529.10.1111/j.1462-5822.2009.01414.xSearch in Google Scholar PubMed PubMed Central

Sandler, H., Kreth, J., Timmers, H.T.M., and Stoecklin, G. (2011). Not1 mediates recruitment of the deadenylase Caf1 to mRNAs targeted for degradation by tristetraprolin. Nucleic Acids Res 39, 4373–4386.10.1093/nar/gkr011Search in Google Scholar PubMed PubMed Central

Schichl, Y.M., Resch, U., Lemberger, C.E., Stichlberger, D., and de Martin, R. (2011). Novel phosphorylation-dependent ubiquitination of tristetraprolin by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1) and tumor necrosis factor receptor-associated factor 2 (TRAF2). J Biol Chem 286, 38466–38477.10.1074/jbc.M111.254888Search in Google Scholar PubMed PubMed Central

Schlapbach, A. and Huppertz, C. (2009). Low-molecular-weight MK2 inhibitors: a tough nut to crack! Future Med Chem 1, 1243–1257.10.4155/fmc.09.98Search in Google Scholar PubMed

Schlapbach, A., Feifel, R., Hawtin, S., Heng, R., Koch, G., Moebitz, H., Revesz, L., Scheufler, C., Velcicky, J., Waelchli, R., et al. (2008). Pyrrolo-pyrimidones: a novel class of MK2 inhibitors with potent cellular activity. Bioorg Med Chem Lett 18, 6142–6146.10.1016/j.bmcl.2008.10.039Search in Google Scholar PubMed

Schottelius, A.J., Zügel, U., Döcke, W.-D., Zollner, T.M., Röse, L., Mengel, A., Buchmann, B., Becker, A., Grütz, G., Naundorf, S., et al. (2010). The role of mitogen-activated protein kinase-activated protein kinase 2 in the p38/TNFα pathway of systemic and cutaneous inflammation. J Invest Dermatol 130, 481–491.10.1038/jid.2009.218Search in Google Scholar PubMed

Schwermann, J., Rathinam, C., Schubert, M., Schumacher, S., Noyan, F., Koseki, H., Kotlyarov, A., Klein, C., and Gaestel, M. (2009). MAPKAP kinase MK2 maintains self-renewal capacity of haematopoietic stem cells. EMBO J 28, 1392–1406.10.1038/emboj.2009.100Search in Google Scholar PubMed PubMed Central

Scott, A.J., O’Dea, K.P., O’Callaghan, D., Williams, L., Dokpesi, J.O., Tatton, L., Handy, J.M., Hogg, P.J., and Takata, M. (2011). Reactive oxygen species and p38 mitogen-activated protein kinase mediate tumor necrosis factor α-converting enzyme (TACE/ADAM-17) activation in primary human monocytes. J Biol Chem 286, 35466–35476.10.1074/jbc.M111.277434Search in Google Scholar PubMed PubMed Central

Sienerth, A.R., Scheuermann, C., Galmiche, A., Rapp, U.R., and Becker, M. (2011). Polycomb group protein Bmi1 negatively regulates IL-10 expression in activated macrophages. Immunol Cell Biol 89, 812–816.10.1038/icb.2010.160Search in Google Scholar PubMed

Stoecklin, G., Lu, M., Rattenbacher, B., and Moroni, C. (2003). A constitutive decay element promotes tumor necrosis factor α mRNA degradation via an AU-rich element-independent pathway. Mol Cell Biol 23, 3506–3515.10.1128/MCB.23.10.3506-3515.2003Search in Google Scholar PubMed PubMed Central

Stoecklin, G., Stubbs, T., Kedersha, N., Wax, S., Rigby, W.F.C., Blackwell, T.K., and Anderson, P. (2004). MK2-induced tristetraprolin:14-3-3 complexes prevent stress granule association and ARE-mRNA decay. EMBO J 23, 1313–1324.10.1038/sj.emboj.7600163Search in Google Scholar PubMed PubMed Central

Swinney, D.C. (2004). Biochemical mechanisms of drug action: what does it take for success? Nat Rev Drug Discov 3, 801–808.10.1038/nrd1500Search in Google Scholar PubMed

Taylor, G.A., Carballo, E., Lee, D.M., Lai, W.S., Thompson, M.J., Patel, D.D., Schenkman, D.I., Gilkeson, G.S., Broxmeyer, H.E., Haynes, B.F., et al. (1996). A pathogenetic role for TNF α in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity 4, 445–454.10.1016/S1074-7613(00)80411-2Search in Google Scholar

Tchen, C.R., Brook, M., Saklatvala, J., and Clark, A.R. (2004). The stability of tristetraprolin mRNA is regulated by mitogen-activated protein kinase p38 and by tristetraprolin itself. J Biol Chem 279, 32393–32400.10.1074/jbc.M402059200Search in Google Scholar PubMed

Tiedje, C., Kotlyarov, A., and Gaestel, M. (2010). Molecular mechanisms of phosphorylation-regulated TTP (tristetraprolin) action and screening for further TTP-interacting proteins. Biochem Soc Trans 38, 1632–1637.10.1042/BST0381632Search in Google Scholar PubMed

Tiedje, C., Ronkina, N., Tehrani, M., Dhamija, S., Laass, K., Holtmann, H., Kotlyarov, A., and Gaestel, M. (2012). The p38/MK2-driven exchange between tristetraprolin and HuR regulates AU-rich element-dependent translation. PLoS Genet 8, e1002977.10.1371/journal.pgen.1002977Search in Google Scholar PubMed PubMed Central

Tietz, A.B.A., Malo, A.A., Diebold, J.J., Kotlyarov, A.A., Herbst, A.A., Kolligs, F.T.F., Brandt-Nedelev, B.B., Halangk, W.W., Gaestel, M.M., Göke, B.B., et al. (2006). Gene deletion of MK2 inhibits TNF-α and IL-6 and protects against cerulein-induced pancreatitis. Am J Physiol Gastrointest Liver Physiol 290, G1298–G1306.10.1152/ajpgi.00530.2005Search in Google Scholar PubMed

Trempolec, N., Dave-Coll, N., and Nebreda, A.R. (2013). SnapShot: p38 MAPK Substrates. Cell 152, 924–924.e1.10.1016/j.cell.2013.01.047Search in Google Scholar PubMed

Velcicky, J., Feifel, R., Hawtin, S., Heng, R., Huppertz, C., Koch, G., Kroemer, M., Moebitz, H., Revesz, L., Scheufler, C., et al. (2010). Novel 3-aminopyrazole inhibitors of MK-2 discovered by scaffold hopping strategy. Bioorg Med Chem Lett 20, 1293–1297.10.1016/j.bmcl.2009.10.138Search in Google Scholar PubMed

Venigalla, R.K.C. and Turner, M. (2012). RNA-binding proteins as a point of convergence of the PI3K and p38 MAPK pathways. Front Immunol 3, 1–9.10.3389/fimmu.2012.00398Search in Google Scholar PubMed PubMed Central

Voncken, J.W., Niessen, H., Neufeld, B., Rennefahrt, U., Dahlmans, V., Kubben, N., Holzer, B., Ludwig, S., and Rapp, U.R. (2005). MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1. J Biol Chem 280, 5178–5187.10.1074/jbc.M407155200Search in Google Scholar PubMed

Ward, B., Seal, B.L., Brophy, C.M., and Panitch, A. (2009). Design of a bioactive cell-penetrating peptide: when a transduction domain does more than transduce. J Pept Sci 15, 668–674.10.1002/psc.1168Search in Google Scholar PubMed PubMed Central

Waterfield, M.R., Zhang, M., Norman, L.P., and Sun, S.-C. (2003). NF-κB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase. Mol Cell 11, 685–694.10.1016/S1097-2765(03)00070-4Search in Google Scholar

Wu, Y., Hannigan, M.O., Kotlyarov, A., Gaestel, M., Wu, D., and Huang, C.-K. (2004). A requirement of MAPKAPK2 in the uropod localization of PTEN during FMLP-induced neutrophil chemotaxis. Biochem Biophys Res Commun 316, 666–672.10.1016/j.bbrc.2004.02.107Search in Google Scholar PubMed

Wu, Y., Zhan, L., Ai, Y., Hannigan, M., Gaestel, M., Huang, C.-K., and Madri, J.A. (2007). MAPKAPK2-mediated LSP1 phosphorylation and FMLP-induced neutrophil polarization. Biochem Biophys Res Commun 358, 170–175.10.1016/j.bbrc.2007.04.104Search in Google Scholar PubMed

Xiao, D., Palani, A., Huang, X., Sofolarides, M., Zhou, W., Chen, X., Aslanian, R., Guo, Z., Fossetta, J., Tian, F., et al. (2013). Conformation constraint of anilides enabling the discovery of tricyclic lactams as potent MK2 non-ATP competitive inhibitors. Bioorg Med Chem Lett 23, 3262–3266.10.1016/j.bmcl.2013.03.109Search in Google Scholar PubMed

Yang, Y.S. and Strittmatter, S.M. (2007). The reticulons: a family of proteins with diverse functions. Genome Biol 8, 1–10.10.1186/gb-2007-8-12-234Search in Google Scholar PubMed PubMed Central

Zaru, R., Ronkina, N., Gaestel, M., Arthur, J.S.C., and Watts, C. (2007). The MAPK-activated kinase Rsk controls an acute Toll-like receptor signaling response in dendritic cells and is activated through two distinct pathways. Nat Immunol 8, 1227–1235.10.1038/ni1517Search in Google Scholar PubMed

Zhao, W., Liu, M., D’Silva, N.J., and Kirkwood, K.L. (2011). Tristetraprolin regulates interleukin-6 expression through p38 MAPK-dependent affinity changes with mRNA 3′ untranslated region. J Interferon Cytokine Res 31, 629–637.10.1089/jir.2010.0154Search in Google Scholar PubMed PubMed Central

Zhu, J., Wu, X., Goel, S., Gowda, N.M., Kumar, S., Krishnegowda, G., Mishra, G., Weinberg, R., Li, G., Gaestel, M., et al. (2009). MAPK-activated protein kinase 2 differentially regulates Plasmodium falciparum glycosylphosphatidylinositol-induced production of tumor necrosis factor-α and interleukin-12 in macrophages. J Biol Chem 284, 15750–15761.10.1074/jbc.M901111200Search in Google Scholar PubMed PubMed Central

Zu, Y.L., Ai, Y., Gilchrist, A., Labadia, M.E., Sha’afi, R.I., and Huang, C.K. (1996). Activation of MAP kinase-activated protein kinase 2 in human neutrophils after phorbol ester or fMLP peptide stimulation. Blood 87, 5287–5296.10.1182/blood.V87.12.5287.bloodjournal87125287Search in Google Scholar