Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2019

Open Access 01-12-2019 | Cytokines | Review

MAPKAPK2: the master regulator of RNA-binding proteins modulates transcript stability and tumor progression

Authors: Sourabh Soni, Prince Anand, Yogendra S. Padwad

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2019

Login to get access

Abstract

The p38 mitogen-activated protein kinase (p38MAPK) pathway has been implicated in a variety of pathological conditions including inflammation and metastasis. Post-transcriptional regulation of genes harboring adenine/uridine-rich elements (AREs) in their 3′-untranslated region (3′-UTR) is controlled by MAPK-activated protein kinase 2 (MAPKAPK2 or MK2), a downstream substrate of the p38MAPK. In response to diverse extracellular stimuli, MK2 influences crucial signaling events, regulates inflammatory cytokines, transcript stability and critical cellular processes. Expression of genes involved in these vital cellular cascades is controlled by subtle interactions in underlying molecular networks and post-transcriptional gene regulation that determines transcript fate in association with RNA-binding proteins (RBPs). Several RBPs associate with the 3′-UTRs of the target transcripts and regulate their expression via modulation of transcript stability. Although MK2 regulates important cellular phenomenon, yet its biological significance in tumor progression has not been well elucidated till date. In this review, we have highlighted in detail the importance of MK2 as the master regulator of RBPs and its role in the regulation of transcript stability, tumor progression, as well as the possibility of use of MK2 as a therapeutic target in tumor management.
Literature
1.
Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Keys JR, Strickler JE, McLaughlin MM. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994;372:739.PubMedCrossRef
2.
Seisenbacher G, Hafen E, Stocker H. MK2-dependent p38b signalling protects Drosophila hindgut enterocytes against JNK-induced apoptosis under chronic stress. PLoS Genet. 2011;7:e1002168.PubMedPubMedCentralCrossRef
3.
Li Y, Inoki K, Vacrasis P, Guan KL. The p38 and MK2 kinase cascade phosphorylates tuberin, the tuberous sclerosis 2 (TSC2) gene product, and enhances its interaction with 14-3-3. J Biol Chem. 2003;278:13663–71.
4.
Wu R, Kausar H, Johnson P, Montoya-Durango DE, Merchant M, Rane MJ. Hsp27 regulates Akt activation and PMN apoptosis by scaffolding MK2 to Akt signal complex. J Biol Chem. 2007;282:21598–608.
5.
Jackson RM, Garcia-Rojas R. Kinase activity, heat shock protein 27 phosphorylation, and lung epithelial cell glutathione. Exp Lung Res. 2008;34:245–62.PubMedCrossRef
6.
Stokoe D, Campbell DG, Nakielny S, Hidaka H, Leevers SJ, Marshall C, Cohen P. MAPKAP kinase-2; a novel protein kinase activated by mitogen-activated protein kinase. EMBO J. 1992;11:3985–94.PubMedPubMedCentralCrossRef
7.
Gurgis FM, 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.PubMedCrossRef
8.
Winzen R, Kracht M, Ritter B, Wilhelm A, Chen CY, Shyu AB, Müller M, Gaestel M, Resch K, Holtmann H. The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism. EMBO J. 1999;18:4969–80.PubMedPubMedCentralCrossRef
9.
Pereira B, Billaud M, Almeida R. RNA-binding proteins in cancer: old players and new actors. Trends Cancer. 2017;3:506–28.PubMedCrossRef
10.
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. 2015;59:3609–34.PubMedPubMedCentralCrossRef
11.
Ashwell JD. The many paths to p38 mitogen-activated protein kinase activation in the immune system. Nat Rev Immunol. 2006;6:532.PubMedCrossRef
12.
Arthur JS, Ley SC. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol. 2013;13:679.PubMedCrossRef
13.
Zu YL, Wu FY, Gilchrist A, Ai YX, Labadia ME, Huang CK. The primary structure of a human MAP kinase activated protein kinase 2. Biochem Biophys Res Commun. 1994;200:1118–24.PubMedCrossRef
14.
Guay J, Lambert H, Gingras-Breton G, Lavoie JN, Huot J, Landry J. Regulation of actin filament dynamics by p38 map kinase-mediated phosphorylation of heat shock protein 27. J Cell Sci. 1997;110:357–68.PubMed
15.
Tan YI, Rouse J, Zhang A, Cariati S, Cohen P, Comb MJ. FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J. 1996;15:4629–42.PubMedPubMedCentralCrossRef
16.
Mahtani KR, Brook M, Dean JL, Sully G, Saklatvala J, Clark AR. Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumor necrosis factor alpha mRNA stability. Mol Cell Biol. 2001;21:6461–9.PubMedPubMedCentralCrossRef
17.
Sudo T, Kawai K, Matsuzaki H, Osada H. p38 mitogen-activated protein kinase plays a key role in regulating MAPKAPK2 expression. Biochem Biophys Res Commun. 2005;337:415–21.PubMedCrossRef
18.
Suarez-Lopez L, Sriram G, Kong YW, Morandell S, Merrick KA, Hernandez Y, Haigis KM, Yaffe MB. MK2 contributes to tumor progression by promoting M2 macrophage polarization and tumor angiogenesis. Proc Natl Acad Sci U S A. 2018;115:4236–44.CrossRef
19.
Dalle-Donne I, Rossi R, Milzani A, Di Simplicio P, Colombo R. The actin cytoskeleton response to oxidants: from small heat shock protein phosphorylation to changes in the redox state of actin itself. Free Radic Biol Med. 2001;31:1624–32.PubMedCrossRef
20.
Hedges JC, Dechert MA, Yamboliev IA, Martin JL, Hickey E, Weber LA, Gerthoffer WT. A role for p38MAPK/HSP27 pathway in smooth muscle cell migration. J Biol Chem. 1999;274:24211–9.PubMedCrossRef
21.
Ray AL, Berggren KL, Restrepo Cruz S, Gan GN, Beswick EJ. Inhibition of MK2 suppresses IL-1β, IL-6, and TNF-α-dependent colorectal cancer growth. Int J Cancer. 2018;142:1702–11.PubMedCrossRef
22.
Stokoe D, Engel K, Campbell DG, Cohen P, Gaestel M. Identification of MAPKAP kinase 2 as a major enzyme responsible for the phosphorylation of the small mammalian heat shock proteins. FEBS Lett. 1992;313:307–13.PubMedCrossRef
23.
Menon MB, Ronkina N, Schwermann J, Kotlyarov A, Gaestel M. Fluorescence-based quantitative scratch wound healing assay demonstrating the role of MAPKAPK-2/3 in fibroblast migration. Cell Motil Cytoskeleton. 2009;66:1041–7.PubMedCrossRef
24.
Neininger A, Kontoyiannis D, Kotlyarov A, Winzen R, Eckert R, Volk HD, Holtmann H, Kollias G, Gaestel M. MK2 targets AU-rich elements and regulates biosynthesis of tumor necrosis factor and interleukin-6 independently at different post-transcriptional levels. J Biol Chem. 2002;277:3065–8.PubMedCrossRef
25.
Manke IA, Nguyen A, Lim D, Stewart MQ, Elia AE, Yaffe MB. MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation. Mol Cell. 2005;17:37–48.PubMedCrossRef
26.
27.
Ronkina N, Menon MB, Schwermann J, Tiedje C, Hitti E, Kotlyarov A, Gaestel M. MAPKAP kinases MK2 and MK3 in inflammation: complex regulation of TNF biosynthesis via expression and phosphorylation of tristetraprolin. Biochem Pharmacol. 2010;80:1915–20.PubMedCrossRef
28.
Stokoe D, Caudwell B, Cohen PT, Cohen P. The substrate specificity and structure of mitogen-activated protein (MAP) kinase-activated protein kinase-2. Biochem J. 1993;296:843–9.PubMedPubMedCentralCrossRef
29.
30.
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.PubMedCrossRef
31.
Tanoue T, Maeda R, Adachi M, Nishida E. Identification of a docking groove on ERK and p38 MAP kinases that regulates the specificity of docking interactions. EMBO J. 2001;20:466–79.PubMedPubMedCentralCrossRef
32.
Ben-Levy R, Leighton IA, Doza YN, Attwood P, Morrice N, Marshall CJ, Cohen P. Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2. EMBO J. 1995;14:5920–30.PubMedPubMedCentralCrossRef
33.
Meng W, Swenson LL, Fitzgibbon MJ, Hayakawa K, ter Haar E, Behrens AE, Fulghum JR, Lippke JA. 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.PubMedCrossRef
34.
Engel K, Schultz H, Martin F, Kotlyarov A, Plath K, Hahn M, Heinemann U, Gaestel M. Constitutive activation of mitogen-activated protein kinase-activated protein kinase 2 by mutation of phosphorylation sites and an A-helix motif. J Biol Chem. 1995;270:27213–21.PubMedCrossRef
35.
Chevalier D, Allen BG. Two distinct forms of MAPKAP kinase-2 in adult cardiac ventricular myocytes. Biochemistry. 2000;39:6145–56.PubMedCrossRef
36.
McLaughlin MM, Kumar S, McDonnell PC, Van Horn S, Lee JC, Livi GP, Young PR. Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase. J Biol Chem. 1996;271:8488–92.PubMedCrossRef
37.
Ronkina N, Kotlyarov A, Dittrich-Breiholz O, Kracht M, Hitti E, Milarski K, Askew R, Marusic S, Lin LL, Gaestel M, Telliez JB. 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.PubMedCrossRef
38.
Cheng R, Felicetti B, Palan S, Toogood-Johnson I, Scheich C, Barker J, Whittaker M, Hesterkamp T. High-resolution crystal structure of human Mapkap kinase 3 in complex with a high affinity ligand. Protein Sci. 2010;19:168–73.PubMed
39.
Ronkina N, Kotlyarov A, Gaestel M. MK2 and MK3–a pair of isoenzymes. Front Biosci. 2008;13:5511–21.PubMedCrossRef
40.
Ehlting C, Ronkina N, Böhmer O, Albrecht U, Bode KA, Lang KS, Kotlyarov A, Radzioch D, Gaestel M, Häussinger D, Bode JG. Distinct functions of 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. 2011;286:24113–24.PubMedPubMedCentralCrossRef
41.
McCarroll SA, Altshuler DM. Copy-number variation and association studies of human disease. Nat Genet. 2007;39:S37.PubMedCrossRef
42.
Shlien A, Malkin D. Copy number variations and cancer susceptibility. Curr Opin Oncol. 2010;22:55–63.PubMedCrossRef
43.
Birner P, Beer A, Vinatzer U, Stary S, Höftberger R, Nirtl N, Wrba F, Streubel B, Schoppmann SF. MAPKAP kinase 2 overexpression influences prognosis in gastrointestinal stromal tumors and associates with copy number variations on chromosome 1 and expression of p38 MAP kinase and ETV1. Clin Cancer Res. 2012;18:1879–87.PubMedCrossRef
44.
Liu B, Yang L, Huang B, Cheng M, Wang H, Li Y, Huang D, Zheng J, Li Q, Zhang X, Ji W. A functional copy-number variation in MAPKAPK2 predicts risk and prognosis of lung cancer. Am J Hum Genet. 2012;91:384–90.PubMedPubMedCentralCrossRef
45.
Yang L, Liu B, Qiu F, Huang B, Li Y, Huang D, Yang R, Yang X, Deng J, Jiang Q, Zhou Y. The effect of functional MAPKAPK2 copy number variation CNV-30450 on elevating nasopharyngeal carcinoma risk is modulated by EBV infection. Carcinogenesis. 2013;35:46–52.PubMedCrossRef
46.
Erdem JS, Skaug V, Haugen A, Zienolddiny S. Loss of MKK3 and MK2 copy numbers in non-small cell lung cancer. J Cancer. 2016;7:512.CrossRef
47.
Kotlyarov A, Neininger A, Schubert C, Eckert R, Birchmeier C, Volk HD, Gaestel M. MAPKAP kinase 2 is essential for LPS-induced TNF-α biosynthesis. Nature Cell Biol. 1999;1:94.PubMedCrossRef
48.
Weber HO, Ludwig RL, Morrison D, Kotlyarov A, Gaestel M, Vousden KH. HDM2 phosphorylation by MAPKAP kinase 2. Oncogene. 2005;24:1965–72.PubMedCrossRef
49.
Morandell S, Reinhardt HC, Cannell IG, Kim JS, Ruf DM, Mitra T, Couvillon AD, Jacks T, Yaffe MB. A reversible gene-targeting strategy identifies synthetic lethal interactions between MK2 and p53 in the DNA damage response in vivo. Cell Rep. 2013;5:868–77.PubMedPubMedCentralCrossRef
50.
Xu L, Chen S, Bergan RC. MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer. Oncogene. 2006;25:2987.PubMedCrossRef
51.
Stoecklin G, Stubbs T, Kedersha N, Wax S, Rigby WF, Blackwell TK, Anderson P. MK2-induced tristetraprolin: 14-3-3 complexes prevent stress granule association and ARE-mRNA decay. EMBO J. 2004;23:1313–24.PubMedPubMedCentralCrossRef
52.
Bulavin DV, Saito S, Hollander MC, Sakaguchi K, Anderson CW, Appella E, Fornace AJ. Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. EMBO J. 1999;18:6845–54.PubMedPubMedCentralCrossRef
53.
Ringshausen I, O'Shea CC, Finch AJ, Swigart LB, Evan GI. Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo. Cancer Cell. 2006;10:501–14.PubMedCrossRef
54.
Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB. p53-deficient cells rely on ATM-and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell. 2007;11:175–89.PubMedPubMedCentralCrossRef
55.
Manetti F. LIM kinases are attractive targets with many macromolecular partners and only a few small molecule regulators. Med Res Rev. 2012;32:968–98.PubMedCrossRef
56.
Rogalla T, Ehrnsperger M, Preville X, Kotlyarov A, Lutsch G, Ducasse C, Paul C, Wieske M, Arrigo AP, Buchner J, Gaestel M. Regulation of Hsp27 oligomerization, chaperone function, and protective activity against oxidative stress/tumor necrosis factor α by phosphorylation. J Biol Chem. 1999;274:18947–56.PubMedCrossRef
57.
Kotlyarov A, Yannoni Y, Fritz S, Laaß K, Telliez JB, Pitman D, Lin LL, Gaestel M. Distinct cellular functions of MK2. Mol Cellular Biol. 2002;22:4827–35.CrossRef
58.
Kumar B, Koul S, Petersen J, Khandrika L, Hwa JS, Meacham RB, Wilson S, Koul HK. p38 mitogen-activated protein kinase–driven MAPKAPK2 regulates invasion of bladder cancer by modulation of MMP-2 and MMP-9 activity. Cancer Res. 2010;70:832–41.PubMedCrossRef
59.
60.
61.
Johansen C, Vestergaard C, Kragballe K, Kollias G, Gaestel M, Iversen L. MK2 regulates the early stages of skin tumor promotion. Carcinogenesis. 2009;30:2100–8.PubMedCrossRef
62.
Riley T, Sontag E, Chen P, Levine A. Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol. 2008;9:402.PubMedCrossRef
63.
Kumar B, Sinclair J, Khandrika L, Koul S, Wilson S, Koul HK. Differential effects of MAPKs signaling on the growth of invasive bladder cancer cells. Int J Oncol. 2009;34:1557–64.PubMed
64.
Shi Y, Massagué J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell. 2003;113:685–700.PubMedCrossRef
65.
66.
Hayes SA, Huang X, Kambhampati S, Platanias LC, Bergan RC. p38 MAP kinase modulates Smad-dependent changes in human prostate cell adhesion. Oncogene. 2003;22:4841.PubMedCrossRef
67.
Cheruku HR, Mohamedali A, Cantor DI, Tan SH, Nice EC, Baker MS. Transforming growth factor-β, MAPK and Wnt signaling interactions in colorectal cancer. EuPA Open Proteom. 2015;8:104–15.CrossRef
68.
Shaw G, Kamen R. A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell. 1986;46:659–67.PubMedCrossRef
69.
Anderson P. Post-transcriptional regulons coordinate the initiation and resolution of inflammation. Nat Rev Immunol. 2010;10:24.PubMedCrossRef
70.
71.
Sanduja S, Dixon DA. Tristetraprolin and E6-AP: killing the messenger in cervical cancer. Cell Cycle. 2010;9:3135–6.PubMedCrossRef
72.
Bakheet T, Williams BR, Khabar KS. ARED 3.0: the large and diverse AU-rich transcriptome. Nucleic Acids Res. 2006;34:D111–4.PubMedCrossRef
73.
Halees AS, El-Badrawi R, Khabar KS. ARED organism: expansion of ARED reveals AU-rich element cluster variations between human and mouse. Nucleic Acids Res. 2007;36:D137–40.PubMedPubMedCentralCrossRef
74.
Khabar KS. The AU-rich transcriptome: more than interferons and cytokines, and its role in disease. J Interf Cytokine Res. 2005;25:1–10.CrossRef
75.
DeMaria CT, Brewer G. AUF1 binding affinity to a+ U-rich elements correlates with rapid mRNA degradation. J Biol Chem. 1996;271:12179–84.PubMedCrossRef
76.
Janga SC, Mittal N. Construction, structure and dynamics of post-transcriptional regulatory network directed by RNA-binding proteins. In: RNA infrastructure and networks. Springer: New York; 2011. p. 103–17.CrossRef
77.
Chen CY, Shyu AB. AU-rich elements: characterization and importance in mRNA degradation. Trends Biochem Sci. 1995;20:465–70.PubMedCrossRef
78.
Khabar KS. Hallmarks of cancer and AU-rich elements. Wiley Interdiscip Rev RNA. 2017;8:e1368.
79.
Bollig F, Winzen R, Kracht M, Ghebremedhin B, Ritter B, Wilhelm A, Resch K, Holtmann H. Evidence for general stabilization of mRNAs in response to UV light. Eur J Biochem. 2002;269:5830–9.PubMedCrossRef
80.
Wilusz CJ, Wormington M, Peltz SW. The cap-to-tail guide to mRNA turnover. Nature reviews Mol Cell Biol. 2001;2:237.CrossRef
81.
82.
Hogan DJ, Riordan DP, Gerber AP, Herschlag D, Brown PO. Diverse RNA-binding proteins interact with functionally related sets of RNAs, suggesting an extensive regulatory system. PLoS Biol. 2008;6:e255.PubMedPubMedCentralCrossRef
83.
Stumpo DJ, Lai WS, Blackshear PJ. Inflammation: cytokines and RNA-based regulation. Wiley Interdiscip Rev RNA 2010;1:60–80.
84.
85.
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.PubMedPubMedCentralCrossRef
86.
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.PubMedCrossRef
87.
88.
Turner M, Hodson DJ. An emerging role of RNA-binding proteins as multifunctional regulators of lymphocyte development and function. In Advances in Immunology, Academic Press. 2012;115:161–85.CrossRef
89.
Anderson P. Intrinsic mRNA stability helps compose the inflammatory symphony. Nat Immunol. 2009;10:233.PubMedCrossRef
90.
Sengupta S, Jang BC, Wu MT, Paik JH, Furneaux H, Hla T. The RNA-binding protein HuR regulates the expression of cyclooxygenase-2. J Biol Chem. 2003;278:25227–33.PubMedCrossRef
91.
Hao S, Baltimore D. The stability of mRNA influences the temporal order of the induction of genes encoding inflammatory molecules. Nat Immunol. 2009;10:281.PubMedPubMedCentralCrossRef
92.
93.
Kim MY, Hur J, Jeong SJ. Emerging roles of RNA and RNA-binding protein network in cancer cells. BMB Rep. 2009;42:125–30.PubMedCrossRef
94.
Silvera D, Formenti SC, Schneider RJ. Translational control in cancer. Nat Rev Cancer. 2010;10:254–66.PubMedCrossRef
95.
Chrestensen CA, Schroeder MJ, Shabanowitz J, Hunt DF, Pelo JW, Worthington MT, Sturgill TW. MAPKAP kinase 2 phosphorylates tristetraprolin on in vivo sites including Ser178, a site required for 14-3-3 binding. J Biol Chem. 2004;279:10176–84.PubMedCrossRef
96.
Carballo E, Lai WS, Blackshear PJ. Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability. Blood. 2000;95:1891–9.PubMed
97.
Brooks SA, Blackshear PJ. Tristetraprolin (TTP): interactions with mRNA and proteins, and current thoughts on mechanisms of action. Biochim Biophys Acta Gene Regul Mech. 1829;2013:666–79.
98.
Taylor GA, Carballo E, Lee DM, Lai WS, Thompson MJ, Patel DD, Schenkman DI, Gilkeson GS, Broxmeyer HE, Haynes BF, Blackshear PJ. A pathogenetic role for TNFα in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity. 1996;4:445–54.PubMedCrossRef
99.
Lai WS, Carballo E, Strum JR, Kennington EA, Phillips RS, Blackshear PJ. Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor alpha mRNA. Mol Cell Biol. 1999;19:4311–23.PubMedPubMedCentralCrossRef
100.
Marchese FP, Aubareda A, Tudor C, Saklatvala J, Clark AR, Dean JL. MAPKAP kinase 2 blocks tristetraprolin-directed mRNA decay by inhibiting CAF1 deadenylase recruitment. J Biol Chem. 2010;jbc:M110.
101.
Brook M, Tchen CR, Santalucia T, McIlrath J, Arthur JS, Saklatvala J, Clark AR. Posttranslational regulation of tristetraprolin subcellular localization and protein stability by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways. Mol Cell Biol. 2006;26:2408–18.PubMedPubMedCentralCrossRef
102.
Sun L, Stoecklin G, Van Way S, Hinkovska-Galcheva V, Guo RF, Anderson P, Shanley TP. Tristetraprolin (TTP)-14-3-3 complex formation protects TTP from dephosphorylation by protein phosphatase 2a and stabilizes tumor necrosis factor-α mRNA. J Biol Chem. 2007;282:3766–77.PubMedCrossRef
103.
Clement SL, Scheckel C, Stoecklin G, Lykke-Andersen J. Phosphorylation of tristetraprolin by MK2 impairs AU-rich element mRNA decay by preventing deadenylase recruitment. Mol Cell Biol. 2011;31:256–66.PubMedCrossRef
104.
Sandler H, Stoecklin G. Control of mRNA decay by phosphorylation of tristetraprolin. Biochem Soc Trans. 2008;36:491–6.PubMedCrossRef
105.
Deleault KM, Skinner SJ, Brooks SA. Tristetraprolin regulates TNF TNF-α mRNA stability via a proteasome dependent mechanism involving the combined action of the ERK and p38 pathways. Mol Immunol. 2008;45:13–24.PubMedCrossRef
106.
Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity. 1999;10:387–98.PubMedCrossRef
107.
Zhao W, Liu M, D'Silva NJ, Kirkwood KL. Tristetraprolin regulates interleukin-6 expression through p38 MAPK-dependent affinity changes with mRNA 3′ untranslated region. J Interf Cytokine Res. 2011;31:629–37.CrossRef
108.
Van Tubergen E, Vander Broek R, Lee J, Wolf G, Carey T, Bradford C, Prince M, Kirkwood KL, D’silva NJ. Tristetraprolin regulates IL-6, which is correlated with tumor progression in patients with head and neck squamous cell carcinoma. Cancer. 2011;117:2677–89.PubMedCrossRef
109.
Van Tubergen EA, Banerjee R, Liu M, Vander Broek RJ, Light E, Kuo S, Feinberg S, Willis AL, Wolf GT, Carey TE, Bradford CR. Inactivation or loss of TTP promotes invasion in head and neck cancer via transcript stabilization and secretion of MMP9, MMP2 and IL-6. Clin Cancer Res. 2013;19:1169–79.PubMedPubMedCentralCrossRef
110.
Lai WS, Parker JS, Grissom SF, Stumpo DJ, Blackshear PJ. Novel mRNA targets for tristetraprolin (TTP) identified by global analysis of stabilized transcripts in TTP-deficient fibroblasts. Mol Cell Biol. 2006;26:9196–208.PubMedPubMedCentralCrossRef
111.
Al-Souhibani N, Al-Ahmadi W, Hesketh JE, Blackshear PJ, Khabar KS. The RNA-binding zinc-finger protein tristetraprolin regulates AU-rich mRNAs involved in breast cancer-related processes. Oncogene. 2010;29:4205.PubMedPubMedCentralCrossRef
112.
Abdelmohsen K, Gorospe M. Posttranscriptional regulation of cancer traits by HuR. Wiley Interdiscip Rev RNA 2010;1:214–229.
113.
Kakuguchi W, Kitamura T, Kuroshima T, Ishikawa M, Kitagawa Y, Totsuka Y, Shindoh M, Higashino F. HuR knockdown changes the oncogenic potential of oral cancer cells. Mol Cancer Res. 2010;8:520–8.PubMedCrossRef
114.
Hasegawa H, Kakuguchi W, Kuroshima T, Kitamura T, Tanaka S, Kitagawa Y, Totsuka Y, Shindoh M, Higashino F. HuR is exported to the cytoplasm in oral cancer cells in a different manner from that of normal cells. Br J Cancer. 2009;100:1943.PubMedPubMedCentralCrossRef
115.
Wu T, Shi JX, Geng S, Zhou W, Shi Y, Su X. The MK2/HuR signaling pathway regulates TNF-α-induced ICAM-1 expression by promoting the stabilization of ICAM-1 mRNA. BMC Pulm Med. 2016;16:84–94.PubMedPubMedCentralCrossRef
116.
Doller A, Pfeilschifter J, Eberhardt W. Signalling pathways regulating nucleo-cytoplasmic shuttling of the mRNA-binding protein HuR. Cell Signal. 2008;20:2165–73.PubMedCrossRef
117.
Guo X, Hartley RS. HuR contributes to cyclin E1 deregulation in MCF-7 breast cancer cells. Cancer Res. 2006;66:7948–56.PubMedCrossRef
118.
Papadaki O, Milatos S, Grammenoudi S, Mukherjee N, Keene JD, Kontoyiannis DL. Control of thymic T cell maturation, deletion and egress by the RNA-binding protein HuR. J Immunol. 2009;182:6779–88.PubMedCrossRef
119.
Heinonen M, Fagerholm R, Aaltonen K, Kilpivaara O, Aittomäki K, Blomqvist C, Heikkilä P, Haglund C, Nevanlinna H, Ristimäki A. Prognostic role of HuR in hereditary breast cancer. Clin Cancer Res. 2007;13:6959–63.PubMedCrossRef
120.
Nabors LB, Gillespie GY, Harkins L, King PH. HuR, a RNA stability factor, is expressed in malignant brain tumors and binds to adenine-and uridine-rich elements within 3′ untranslated regions of cytokine and angiogenic factor mRNAs. Cancer Res. 2001;61:2154–61.PubMed
121.
Gurgis FM, Yeung YT, Tang MX, Heng B, Buckland M, Ammit AJ, Haapasalo J, Haapasalo H, Guillemin GJ, Grewal T, Munoz L. The p38-MK2-HuR pathway potentiates EGFRvIII–IL-1β-driven IL-6 secretion in glioblastoma cells. Oncogene. 2015;34:2934–42.PubMedCrossRef
122.
Abdelmohsen K, Lal A, Kim HH, Gorospe M. Posttranscriptional orchestration of an anti-apoptotic program by HuR. Cell Cycle. 2007;6:1288–92.PubMedCrossRef
123.
Meisner NC, Filipowicz W. Properties of the regulatory RNA-binding protein HuR and its role in controlling miRNA repression. In: Regulation of microRNAs. New York: Springer; 2010. p. 106–23.CrossRef
124.
Choi HJ, Yang H, Park SH, Moon Y. HuR/ELAVL1 RNA binding protein modulates interleukin-8 induction by muco-active ribotoxin deoxynivalenol. Toxicol Appl Pharmacol. 2009;240:46–54.PubMedCrossRef
125.
von Roretz C, Gallouzi IE. Decoding ARE-mediated decay: is microRNA part of the equation? J Cell Biol. 2008;181:189–94.CrossRef
126.
Cha JD, Li S, Cha IH. Association between expression of embryonic lethal abnormal vision-like protein HuR and cyclooxygenase-2 in oral squamous cell carcinoma. Head Neck. 2011;33:627–37.PubMedCrossRef
127.
Gratacós FM, Brewer G. The role of AUF1 in regulated mRNA decay. Wiley Interdiscip Rev RNA. 2010;1:457–473.
128.
Loflin P, Chen CY, Shyu AB. Unraveling a cytoplasmic role for hnRNP D in the in vivo mRNA destabilization directed by the AU-rich element. Genes Dev. 1999;13:1884–97.PubMedPubMedCentralCrossRef
129.
130.
Hitti E, Bakheet T, Al-Souhibani N, Moghrabi W, Al-Yahya S, Al-Ghamdi M, Al-Saif M, Shoukri MM, Lánczk A, Grépin R, Győrffy B. Systematic analysis of AU-rich element expression in cancer reveals common functional clusters regulated by key RNA-binding proteins. Cancer Res. 2016;76:4068–80.PubMedCrossRef
131.
Yoo PS, Mulkeen AL, Silva T, Schmitz J, Tai N, Uchio EM, Chu E, Cha CH. RNA-binding protein HUR regulates VEGF expression in human colorectal cancer cells. J Surg Res. 2006;130:219–20.CrossRef
132.
Frevel MA, Bakheet T, Silva AM, Hissong JG, Khabar KS, Williams BR. p38 mitogen-activated protein kinase-dependent and-independent signaling of mRNA stability of AU-rich element-containing transcripts. Mol Cell Biol. 2003;23:425–36.PubMedPubMedCentralCrossRef
133.
Herman AB, Autieri MV. Inflammation-regulated mRNA stability and the progression of vascular inflammatory diseases. Clin Sci. 2017;131:2687–99.CrossRef
134.
Chang CI, Xu BE, Akella R, Cobb MH, Goldsmith EJ. Crystal structures of MAP kinase p38 complexed to the docking sites on its nuclear substrate MEF2A and activator MKK3b. Mol Cell. 2002;9:1241–9.PubMedCrossRef
135.
Lukas SM, Kroe RR, Wildeson J, Peet GW, Frego L, Davidson W, Ingraham RH, Pargellis CA, Labadia ME, Werneburg BG. Catalysis and function of the p38α-MK2a signaling complex. Biochemistry. 2004;43:9950–60.PubMedCrossRef
136.
137.
Allen M, Svensson L, Roach M, Hambor J, McNeish J, Gabel CA. Deficiency of the stress kinase p38α 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.PubMedPubMedCentralCrossRef
138.
Streicher JM, Ren S, Herschman H, Wang Y. MAPKactivated protein kinase-2 in cardiac hypertrophy and cyclooxygenase- 2 regulation in heart. Circ Res. 2010;106:1434–43.PubMedPubMedCentralCrossRef
139.
Vittal R, Fisher A, Gu H, Mickler EA, Panitch A, Lander C, Cummings OW, Sandusky GE, Wilkes DS. Peptidemediated inhibition of MK2 ameliorates bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 2013;49:47–57.PubMedPubMedCentralCrossRef
140.
Mourey RJ, Burnette BL, Brustkern SJ, Daniels JS, Hirsch JL, Hood WF, Meyers MJ, Mnich SJ, Pierce BS, Saabye MJ, Schindler JF. 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. 2010;333:797–807.PubMedCrossRef
141.
Edmunds JJ, Talanian RV. MAPKAP kinase 2 (MK2) as a target for anti-inflammatory drug discovery. Anti-Inflammatory Drug Discovery. 2012;26:158.CrossRef
142.
Swinney DC. Biochemical mechanisms of drug action: what does it take for success? Nat Rev Drug Discov. 2004;3:801.PubMedCrossRef
143.
Huang X, Zhu X, Chen X, Zhou W, Xiao D, Degrado S, Aslanian R, Fossetta J, Lundell D, Tian F, Trivedi P. 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. Bioorganic Med Chem Lett. 2012;22:65–70.CrossRef
144.
Watterson DM, Grum-Tokars VL, Roy SM, Schavocky JP, Bradaric BD, Bachstetter AD, Xing B, Dimayuga E, Saeed F, Zhang H, Staniszewski A. Development of novel in vivo chemical probes to address CNS protein kinase involvement in synaptic dysfunction. PLoS One. 2013;8:e66226.PubMedPubMedCentralCrossRef
145.
Wang C, Hockerman S, Jacobsen EJ, Alippe Y, Selness SR, Hope HR, Hirsch JL, Mnich SJ, Saabye MJ, Hood WF, Bonar SL. Selective inhibition of the p38α MAPK–MK2 axis inhibits inflammatory cues including inflammasome priming signals. J Exp Med. 2018;215:1315–25.PubMedPubMedCentralCrossRef
146.
Hitti E, Iakovleva T, Brook M, Deppenmeier S, Gruber AD, Radzioch D, Clark AR, Blackshear PJ, Kotlyarov A, Gaestel M. 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.PubMedPubMedCentralCrossRef
147.
Blasius M, Wagner SA, Choudhary C, Bartek J, Jackson SP. A quantitative 14-3-3 interaction screen connects the nuclear exosome targeting complex to the DNA damage response. Genes Dev. 2014;28:1977–82.PubMedPubMedCentralCrossRef
148.
Liu Q, Guntuku S, Cui XS, Matsuoka S, Cortez D, Tamai K, Luo G, Carattini-Rivera S, DeMayo F, Bradley A, Donehower LA. Chk1 is an essential kinase that is regulated by Atr and required for the G2/M DNA damage checkpoint. Genes Dev. 2000;14:1448–59.PubMedPubMedCentralCrossRef
149.
Ray AL, Castillo EF, Morris KT, Nofchissey RA, Weston LL, Samedi VG, Hanson JA, Gaestel M, Pinchuk IV, Beswick EJ. Blockade of MK 2 is protective in inflammation-associated colorectal cancer development. Int J Cancer. 2016;138:770–5.PubMedCrossRef
150.
Berggren K, Cruz SR, Hixon MD, Cowan A, Ozbun MA, Keysar S, Jimeno A, Ness SA, McCance DJ, Beswick EJ, Gan GN. Inhibition of MK2 decreases inflammatory cytokine production and tumor volumes in HPV-positive and HPV-negative models of head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2018;100:1372–3.CrossRef
151.
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, Kazemier B. Structure-based lead identification of ATP-competitive MK2 inhibitors. Bioorganic Med Chem Lett. 2011;21:3818–22.CrossRef
152.
Anderson DR, Meyers MJ, Vernier WF, Mahoney MW, Kurumbail RG, Caspers N, Poda GI, Schindler JF, Reitz DB, Mourey RJ. Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). J Med Chem. 2007;50:2647–54.PubMedCrossRef
153.
Anderson DR, Meyers MJ, Kurumbail RG, Caspers N, Poda GI, Long SA, Pierce BS, Mahoney MW, Mourey RJ, Parikh MD. Benzothiophene inhibitors of MK2. Part 2: improvements in kinase selectivity and cell potency. Bioorganic Med Chem Lett. 2009;19:4882–4.CrossRef
154.
Wu JP, Wang J, Abeywardane A, Andersen D, Emmanuel M, Gautschi E, Goldberg DR, Kashem MA, Lukas S, Mao W, Martin L. The discovery of carboline analogs as potent MAPKAP-K2 inhibitors. Bioorganic Med Chem Lett. 2007;17:4664–9.CrossRef
155.
Hillig RC, Eberspaecher U, Monteclaro F, Huber M, Nguyen D, Mengel A, Muller-Tiemann B, Egner U. Structural basis for a high affinity inhibitor bound to protein kinase MK2. J Mol Biol. 2007;69:735–45.CrossRef
156.
Velcicky J, Feifel R, Hawtin S, Heng R, Huppertz C, Koch G, Kroemer M, Moebitz H, Revesz L, Scheufler C, Schlapbach A. Novel 3-aminopyrazole inhibitors of MK-2 discovered by scaffold hopping strategy. Bioorganic Med Chem Lett. 2010;20:1293–7.CrossRef
157.
Revesz L, Schlapbach A, Aichholz R, Dawson J, Feifel R, Hawtin S, Littlewood-Evans A, Koch G, Kroemer M, Möbitz H, Scheufler C. In vivo and in vitro SAR of tetracyclic MAPKAP-K2 (MK2) inhibitors. Part II. Bioorganic Med Chem Lett. 2010;20:4719–23.CrossRef
158.
Argiriadi MA, Ericsson AM, Harris CM, Banach DL, Borhani DW, Calderwood DJ, Demers MD, DiMauro J, Dixon RW, Hardman J, Kwak S. 2, 4-Diaminopyrimidine MK2 inhibitors. Part I: observation of an unexpected inhibitor binding mode. Bioorganic Med Chem Lett. 2010;20:330–3.CrossRef
159.
Gaoni Y, Mechoulam R. Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc. 1964;86:1646–7.CrossRef
160.
161.
Xiao D, Palani A, Huang X, Sofolarides M, Zhou W. Chen X, Aslanian R, Guo Z, Fossetta J, Tian F, Trivedi P. Conformation constraint of anilides enabling the discovery of tricyclic lactams as potent MK2 non-ATP competitive inhibitors. Bioorganic Med Chem Lett. 2013;23:3262–3266.
162.
Rao AU, Xiao D, Huang X, Zhou W, Fossetta J, Lundell D, Tian F, Trivedi P, Aslanian R, Palani A. Facile synthesis of tetracyclic azepine and oxazocine derivatives and their potential as MAPKAP-K2 (MK2) inhibitors. Bioorganic Med Chem Lett. 2012;22:1068–72.CrossRef
Metadata
Title
MAPKAPK2: the master regulator of RNA-binding proteins modulates transcript stability and tumor progression
Authors
Sourabh Soni
Prince Anand
Yogendra S. Padwad
Publication date
01-12-2019
Publisher
BioMed Central
Keyword
Cytokines
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2019
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-019-1115-1

Other articles of this Issue 1/2019

Journal of Experimental & Clinical Cancer Research 1/2019 Go to the issue

Research

CD36 mediates palmitate acid-induced metastasis of gastric cancer via AKT/GSK-3β/β-catenin pathway

Research

Notch1 signaling in NOTCH1-mutated mantle cell lymphoma depends on Delta-Like ligand 4 and is a potential target for specific antibody therapy

Correction

Correction to: Tumor-associated neutrophils induce EMT by IL-17a to promote migration and invasion in gastric cancer cells

Research

GSTZ1 deficiency promotes hepatocellular carcinoma proliferation via activation of the KEAP1/NRF2 pathway

Research

Preclinical evaluation of 3D185, a novel potent inhibitor of FGFR1/2/3 and CSF-1R, in FGFR-dependent and macrophage-dominant cancer models

Correction

Correction to: EBV-miR-BART8-3p induces epithelial-mesenchymal transition and promotes metastasis of nasopharyngeal carcinoma cells through activating NF-κB and Erk1/2 pathways
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits