Abstract
The p38/MK2 pathway regulates a wide range of biological functions, and thus has most been explored as a therapeutic target for inhibition of severe and chronic inflammatory diseases. Till date, several p38 inhibitors with potent anti-inflammatory effects in pre-clinical models have been discovered, but most of them have failed in clinics due to serious systemic toxicity issues.
MK2 is a serine-threonine kinase downstream to p38 and is activated directly through phosphorylation of p38 under stress and inflammatory stimulus. MK2 has been shown to be a direct and essential component in regulating the biosynthesis of pro-inflammatory cytokines. Disruption of MK2 signaling leads to a significant reduction in the level of several pro-inflammatory cytokine production. For these reasons, MK2 has been identified as an alternate molecular target in order to block the pathway with an assumption that this approach would show similar efficacy as that of p38 inhibitors with lesser toxicity concerns.
This review briefly summarizes the molecular structure of MK2 and major biological functions in context with its pharmacological modulation to address various inflammatory diseases. It also discusses the points of advantages over p38 inhibition along with recent update in the development of small molecule MK2 inhibitors.
Similar content being viewed by others
References
Gaestel M, Mengel A, Bothe U, Asadullah K. Protein kinases as small molecule inhibitor targets in inflammation. Curr Med Chem 2007;14:2214–34.
Kumar S, Boehm J, Lee JC. p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov 2003;2(9):717–26.
Lee JC, Kumar S, Griswold DE, Underwood DC, Votta BJ, Adams JL. Inhibition of p38 MAP kinase as a therapeutic strategy. Immunopharmacology 2000;47:185–201.
Mittelstadt PR, Salvador JM, Fornace Jr. AJ, Ashwell JD. Activating p38 MAPK — new tricks for an old kinase. Cell Cycle 2005;4(9):1189–92.
Saklatvala J. The p38 MAP kinase pathway as a therapeutic target in inflammatory disease. Curr Opin Pharmacol 2004;4(4):372–7.
Dominguez C, Powers DA, Tamayo N. p38 MAP kinase inhibitors: many are made, but few are chosen. Curr Opin Drug Discov Dev 2005;8:421–30.
Zhang J, Shen B, Lin A. Novel strategies for inhibition of the p38 MAPK pathway. Trends Pharmacol Sci 2007;28(6):286–95.
Hegen M, Gaestel M, Nickerson-Nutter CL, Lin LL, Telliez JB. MAPKAP kinase 2-deficient mice are resistant to collagen-induced arthritis. J Immunol 2006;177:1913–7.
Kang JS, Kim HM, Choi IY, Han S-B, Yoon YD, Lee H, et al. DBM1285 suppresses tumor necrosis factor production by blocking p38 mitogen-activated protein kinase/mitogen-activated protein kinase-activated protein kinase 2 signaling pathway. J Pharmacol Exp Ther 2010;334:657–64.
Lee JC, Kassis S, Kumar S, Badger A, Adams JL. p38 mitogen-activated protein kinase inhibitors-mechanisms and therapeutic potentials. Pharmacol Ther 1999;82(2–3):389–97.
Revesz L, Blum E, Padova FED. Novel p38 inhibitors with potent oral efficacy in several models of rheumatoid arthritis. Bioorg Med Chem Lett 2004;4(13):3595–9.
Broom OJ, Widjaya B, Troelsen J, Olsen J, Nielsen OH. Mitogen activated protein kinases: a role in inflammatory bowel diseases? Clin Exp Immunol 2009;158:272–80.
Moens U, Kostenko S, Sveinbjornsson B. The role of mitogen activated protein kinase-activated protein kinases (MAPKAPKs) in inflammation. Genes 2013;4:101–33.
Chopra P, Kanoje V, Semwal A, Ray A. Therapeutic potential of inhaled p38 mitogen-activated protein kinase inhibitors for inflammatory pulmonary diseases. Expert Opin Investig Drugs 2008;17(10):1411–25.
Moretto N, Bertolini S, Iadicicco C, Marchini G, Kaur M, Volpi G, et al. Cigarette smoke and its component acrolein augment IL-8/CXCL8 mRNA stability via p38 MAPK/MK2 signaling in human pulmonary cells. Am J Physiol Lung Cell Mol Physiol 2012;303:L929–38.
Dambach DM. Potential adverse effects associated with inhibition of p38 α/β MAP kinases. Curr Top Med Chem 2005;5(10):929–39.
Duraisamy S, Bajpai M, Bughani U, Dastidar SG, Ray A, Chopra P. MK2: a novel molecular target for anti-inflammatory therapy. Expert Opin Ther Targets 2008;12(8):921–36.
Allen M, Svensson L, Roach M, Hambor J, McNeish J, Gabel CA. Deficiency of the stress kinase p38 results in embryonic lethality: characterization of the kinase dependence of stress responses of enzyme deficient embryonic stem cells. J Exp Med 2000;191:859–70.
Fiore M, Forli S, Manetti F. Targeting mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2, MK2): medicinal chemistry efforts to lead small molecule inhibitors to clinical trials. J Med Chem 2016;59(8):3609–34.
Hitti E, Iakovleva T, Brook M, Deppenmeier S, Gruber AD, Radzioch D, et al. 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 2006;26:2399–407.
Ronkina N, Menon MB, Schwermann J, Tiedje C, Hitti E, Kotlyarov A, et al. MAPKAP kinases MK2 and MK3 in inflammation: complex regulation of TNF biosynthesis via expression and phosphorylation of tristetraprolin. Biochem Pharmacol 2010;80:1915–20.
White A, Pargellis CA, Studts JM, Werneburg BG, Farmer BT. Molecular basis of MAPK-activated protein kinase 2:p38 assembly. Proc Natl Acad Sci U S A 2007;104:6353–8.
Meng W, Swenson LL, Fitzgibbon MJ, Hayakawa K, Ter Haar E, Behrens AE, et al. Structure of mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 suggests a bifunctional switch that couples kinase activation with nuclear export. J Biol Chem 2002;277:37401–5.
Neininger A, Thielemann H, Gaestel M. FRET-based detection of different conformations of MK2. EMBO Rep 2001;2:703–8.
Ben-Levy R, Hooper S, Wilson R, Paterson HF, Marshall CJ. Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2. Curr Biol 1998;8:1049–57.
Natesan S, Subramaniam R, Bergeron C, Balaz S. Binding affinity prediction for ligands and receptors forming tautomers and ionization species: inhibition of mitogen-activated protein kinase activated protein kinase 2 (MK2). J Med Chem 2012;55:2035–47.
Underwood KW, Parris KD, Federico E, Mosyak L, Czerwinski RM, Shane T, et al. Catalytically active MAPKAP kinase 2 structures in complex with staurosporine and ADP reveal differences with the autoinhibited enzyme. Structure 2003;11:627–36.
Zu YL, Ai T, Huang CK. Characterization of an autoinhibitory domain in human mitogen-activated protein kinase activated protein kinase 2. J Biol Chem 1995;270:202–6.
Ben-Levy R, Leighton IA, Doza YN, Attwood P, Morrice N, Marshall CJ, et al. Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2. EMBO J 1995;14:5920–30.
Kotlyarov A, Yannoni Y, Fritz S, Laab K, Telliez J-B, Pitman D, et al. Distinct cellular functions of MK2. Mol Cell Biol 2002;22(13):4827–35.
Ronkina N, Kotlyarov A, Gaestel M. MK2 and MK3 — a pair of isoenzymes? Front Biosci 2008;13:5511–21.
Gaestel M. What goes up must come down: molecular basis of MAPKAP kinase 2/3-dependent regulation of the inflammatory response and its inhibition. Biol Chem 2013;394:1301–15.
Ronkina N, Kotlyarov A, Dittrich-Breiholz O, Kracht M, Hitti E, Milarski K, et al. 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 2007;27:170–81.
Haar Et, Prabakhar P, Liu X, Lepre C. Crystal structure of the p38α-MAPKAP kinase 2 heterodimer. J Biol Chem 2007;282:9733–9.
Anderson DR, Meyers MJ, Kurumbail RG, Caspers N, Poda GI, Long SA, et al. Benzothiophene inhibitors of MK2. Part 1: structure-activity relationships, assessment of selectivity and cellular potency. Bioorg Med Chem Lett 2009;19:4878–81.
Anderson DR, Meyers MJ, Vernier WF, Mahoney MW, Kurumbail RG, Caspers N, et al. Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). J Med Chem 2007;50:2647–54.
Mourey RJ, Burnette BL, Brustkern SJ, Daniels JS, Hirsch JL, Hood WF, et al. A benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor a production and has oral anti-inflammatory efficacy in acute and chronic models of inflammation. J Pharmacol Exp Ther 2010;333:797–807.
Lee MR, Dominguez C. MAP kinase p38 inhibitors: clinical results and an intimate look at their interactions with p38 protein. Curr Med Chem 2005;12:2979–94.
Stoecklin G, Stubbs T, Kedersha N, Wax S, Rigby WF, Blackwell TK, et al. MK2-induced tristetraprolin: 14-3-3 complexes prevent stress granule association and ARE-mRNA decay. EMBO J 2004;23:1313–24.
Thuraisingam T, Xu YZ, Moisan J. Distinct role of MAPKAPK-2 in the regulation of TNF gene expression by Toll-like receptor 7 and 9 ligands. Mol Immunol 2007;44(14):3482–91.
Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 2011;75:50–83.
Clement SL, Scheckel C, Stoecklin G, Andersen JL. Phosphorylation of tristetraprolin by MK2 impairs AU-rich element mRNA decay by preventing deadenylase recruitment. Mol Cell Biol 2011;31(2):256–66.
Gaestel M. MAPKAP kinases — MKs — two’s company, three’s a crowd. Nat Rev Mol Cell Biol 2006;7:120–30.
Kotlyarov A, Gaestel M. Is MK2 (mitogen-activated protein kinase-activated protein kinase 2) the key for understanding post-transcriptional regulation of gene expression? Biochem Soc Trans 2002;30(6):959–63.
Argiriadi MA, Sousa S, Banach D, Marcotte D, Xiang T, Tomlinson MJ, et al. Rational mutagenesis to support structure-based drug design: MAPKAP kinase 2 as a case study. BMC Struct Biol 2009;9:16–28.
Lehner MD, Schwoebel F, Kotlyarov A. Mitogen-activated protein kinase-activated protein kinase 2-deficient mice show increased susceptibility to Listeria monocytogenes infection. J Immunol 2002;168(9):4667–73.
Ehlting C, Ronkina N, Bohmer O, Albrecht U, Bode KA, Lang KS, et al. Distinct functions of the mitogen-activated protein kinase-activated protein (MAPKAP) kinases MK2 and MK3. J Biol Chem 2011;286(27):24113–24.
Gaestel M, Kotlyarov A, Kracht M. Targeting innate immunity protein kinase signalling in inflammation. Nat Rev Drug Discov 2009;8:480–99.
Gais P, Tiedje C, Altmayr F, Gaestel M, Weighardt H, Holzmann B. TRIF signaling stimulates translation of TNF-a mRNA via prolonged activation of MK2. J Immunol 2010;184:5842–8.
Trentham DE, Townes AS, Kang AH. Autoimmunity type II collagen and experimental model of arthritis. J Exp Med 1977;146:857–68.
Jones SW, Brockbank SM, Clements KM, Good NL, Campbell D, Read SJ, et al. MK2 modulates key biological pathways associated with osteoarthritis disease pathology. Osteoarthr Cartil 2009;17:124–31.
Gorska MM, Liang Q, Stafford SJ, Goplen N, Dharajiya N, Guo L, et al. MK2 controls the level of negative feedback in the NF-kB pathway and is essential for vascular permeability and airway inflammation. J Exp Med 2007;204:1637–52.
Li YY, Yuece B, Cao HM, Lin HX, Lv S, Chen JC, et al. Inhibition of p38/MK2 signaling pathway improves the anti-inflammatory effect of WIN55 on mouse experimental colitis. Lab Invest 2013;93:322–33.
Johansen C, Funding AT, Otkjaer K, Kragballe K, Jensen UB, Medsen M, et al. Protein expression of TNFa in psoriatic skin is regulated at a post-transcriptional level by MAPKAPK-2. J Immunol 2006;176:1431–8.
Funding AT, Johansen C, Gaestel M, Bibby BM, Lilleholt LL, Kragballe K, et al. Reduced oxazolone-induced skin inflammation in MAPKAPK-2 knockout mice. J Investig Dermatol 2009;129:891–8.
Fyhrquist N, Matikainen S, Lauerma A. MK2 signaling: lessons on tissue specificity in modulation of inflammation. J Investig Dermatol 2010;130:342–4.
Schottelius AJ, Zugel U, Docke W, Zollner TM, Rose L, Mengel A, et al. The role of mitogen activated protein kinase-activated protein kinase-2 in the p38/TNF-a pathway of systemic and cutaneous inflammation. J Investig Dermatol 2010;130:481–91.
Culbert AA, Skaper SD, Howlett DR, Evans NA, Facci L, Soden PE, et al. MAPK-activated protein kinase 2 deficiency in microglia inhibits pro-inflammatory mediator release and resultant neurotoxicity. Relevance to neuroinflammation in a transgenic mouse model of Alzheimer disease. J Biol Chem 2006;281:23658–67.
Gurgis FMS, Ziaziaris W, Munoz L. Mitogen-activated protein kinase-activated protein kinase 2 in neuroinflammation, heat shock protein 27 phosphorylation, and cell cycle: role and targeting. Mol Pharmacol 2014;85:345–56.
Bachstetter AD, Xing B, de Almeida L, Dimayuga ER, Watterson DM, Eldik LJV. Microglial p38a MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Ab). J Neuroinflamm 2011;8:79.
Thomas T, Hitti E, Kotlyarov A, Potschka H, Gaestel M. MAP-kinase activated protein kinase 2 expression and activity is induced after neuronal depolarization. Eur J Neurosci 2008;28:642–54.
Goldstein DM, Gabriel T. Pathway to the clinic: inhibition of P38 MAP kinase. A review of ten chemotypes selected for development. Curr Top Med Chem 2005;5:1017–29.
Hammaker D, Firestein GS. “Go upstream, young man”: lessons learned from the p38 saga. Ann Rheum Dis 2010;69(S1):i77–82.
Cheung PC, Campbell DG, Nebreda AR, Cohen P. Feedback control of the protein kinase TAK1 by SAPK2a/p38a. EMBO J 2003;22:5793–805.
Muniyappa H, Das KC. Activation of c-Jun N-Terminal Kinase (JNK) by widely used specific p38 MAPK inhibitor SB202190 and SB203580: a MLK-3 MKK7-dependent mechanism. Cell Signal 2008;20(4):675–83.
Trempolec N, Dave-Coll N, Nebreda AR. SnapShot: p38 MAPK substrates. Cell 2013;152:924.
Ananieva O, Darragh J, Johansen C, Carr JM, McIlrath J, Park JM, et al. The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling. Nat Immunol 2008;9(9):1028–36.
Mudgett JS, Ding J, Guh-Siesel L. Essential role for p38 α mitogen-activated protein kinase in placental angiogenesis. Proc Natl Acad Sci U S A 2000;97(19):10454–9.
Clark AR, Dean JL. The p38MAPK pathway in rheumatoid arthritis: a sideway look. Open Rheumatol J 2012;6:209–19.
Anderson DR, Hegde S, Reinhard E, Gomez L, Vernier WF, Lee L, et al. Aminocyanopyridine inhibitors of mitogen activated protein kinase activated protein kinase 2 (MK-2). Bioorg Med Chem Lett 2005;15:1587–90.
Anderson DR, Meyers MJ, Kurumbail RG, Caspers N, Poda GI, Long SA, et al. Benzothiophene inhibitors of MK2. Part 1: improvements in kinase selectivity and cell potency. Bioorg Med Chem Lett 2009;19:4882–4.
Barf T, Kaptein A, de Wilde S, van der Heijden R, van Someren R, Demont D, et al. Structure-based lead identification of ATP-competitive MK2 inhibitors. Bioorg Med Chem Lett 2011;21:3818–22.
Oubrie A, Kaptein A, de Zwart E, Hoogenboom N, Goorden R, van de Kar B, et al. Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series. Bioorg Med Chem Lett 2012;22:613–8.
Trujillo JI, Meyers MJ, Anderson DR, Hegde S, Mahoney MW, Vernier WF, et al. Novel tetrahydro-β-carboline-1-carboxylic acids as inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2). Bioorg Med Chem Lett 2007;17:4657–63.
Schlapbach A, Huppertz C. Low molecular-weight MK2 inhibitors: a tough nut to crack!. Future Med Chem 2009;1:1243–57.
Hillig RC, Eberspaecher U, Monteclaro F, Huber M, Nguyen D, Mengel A, et al. Structural basis for a high affinity inhibitor bound to protein kinase MK2. J Mol Biol 2007;369:735–45.
Shankar S, Handa R. Biological agents in rheumatoid arthritis. J Postgrad Med 2004;50(4):293–9.
Swinney DC. Biochemical mechanisms of drug action: what does it take for success? Nat Rev Drug Discov 2004;3:801–8.
Swinney DC, Anthony J. How were new medicines discovered? Nat Rev Drug Discov 2011;10:507–19.
Qin J, Dhondi P, Huang X, Aslanian R, Fossetta J, Tian F, et al. Discovery of a potent dihydrooxadiazole series of non-ATP competitive MK2 (MAPKAPK2) inhibitors. ACS Med Chem Lett 2012;3:100–5.
Xiao D, Zhu X, Sofolarides M, Degrado S, Shao N, Rao A, et al. Discovery of a novel series of potent MK2 non-ATP competitive inhibitors using 1,2-substituted azoles as cis-amide isosteres. Bioorg Med Chem Lett 2014;24:3609–13.
Huang X, Zhu X, Chen X, Zhou W, Xiao D, Degrado S, et al. 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 2012;22:65–70.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Singh, R.K., Najmi, A.K. & Dastidar, S.G. Biological functions and role of mitogen-activated protein kinase activated protein kinase 2 (MK2) in inflammatory diseases. Pharmacol. Rep 69, 746–756 (2017). https://doi.org/10.1016/j.pharep.2017.03.023
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1016/j.pharep.2017.03.023