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Gene Review

MAPKAPK2  -  mitogen-activated protein kinase-activated...

Homo sapiens

Synonyms: MAP kinase-activated protein kinase 2, MAPK-activated protein kinase 2, MAPKAP kinase 2, MAPKAP-K2, MAPKAPK-2, ...

Disease relevance of MAPKAPK2


High impact information on MAPKAPK2

  • In several cell lines, however, MAPKAP kinase-2 is activated by sodium arsenite, heat shock, or osmotic stress and not by agonists that activate p42/p44MAPK [7].
  • A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins [7].
  • The RKK, RK, and MAPKAP kinase-2 constitute a new stress-activated signal transduction pathway in vertebrates that is distinct from the classical MAPK cascade [7].
  • Now, new kinases that phosphorylate and inactivate Cdc25 are being discovered, including MAPKAP kinase-2, a component of the p38 stress-activated MAP kinase pathway [8].
  • We propose that MAPKAP kinase-2 is a new member of the DNA damage checkpoint kinase family that functions in parallel with Chk1 and Chk2 to integrate DNA damage signaling responses and cell cycle arrest in mammalian cells [9].
  • MK2 mediated cell-type specific activation of p90 RSK regulate dendritic cell endocytic response to TLR stimulation [10]
  • Depletion of MK2 protected cells from DNA damage-induced death, and MK2-deficient mice displayed decreased apoptosis in the skin upon UV irradiation [11]
  • MK2 regulates autophagy by directly phosphorylating BECN1 [12]
  • DNA damage induced replication fork stalling is regulated by MAPKAPK2  [11]

Chemical compound and disease context of MAPKAPK2


Biological context of MAPKAPK2


Anatomical context of MAPKAPK2

  • To identify substrates of MAPKAPK2 that mediate these responses, a proteomic approach was used in which in vitro phosphorylation of neutrophil lysates by exogenously added active recombinant MAPKAPK2 was followed by protein separation using two-dimensional electrophoresis [21].
  • The ability of MAPKAPK2 to phosphorylate one isoform of p16-Arc suggests a possible mechanism by which the p38 MAPK cascade regulates remodeling of the actin cytoskeleton [21].
  • Wortmannin or a low concentration of SB203580 partially inhibited MAPKAPK2, but did not block mast cell migration [22].
  • The MAPKAPK2 form found in PC12 cells corresponds to variant 2 in the human; this ortholog carries a nuclear translocation signal near its C-terminus [17].
  • The correlation between decreased MAPKAPK-2 phosphorylation and loss of active p38 MAPK in failing human myocytes suggests that decreases in the activation of p38 MAPK alpha, the predominant cardiac isoform, occur prior to end-stage heart failure [23].

Associations of MAPKAPK2 with chemical compounds


Physical interactions of MAPKAPK2

  • Identification of the p16-Arc subunit of the Arp 2/3 complex as a substrate of MAPK-activated protein kinase 2 by proteomic analysis [21].
  • The glucose-stimulated activation of IUF1 DNA binding and MAPKAP kinase-2 (but not the arsenite-induced activation of these proteins) was prevented by wortmannin and LY 294002 at concentrations similar to those that inhibit phosphatidylinositide 3-kinase [27].
  • Phosphorylation of TSC2 by MK2 creates a 14-3-3 binding site and thus regulates the cellular function of the TSC2 tumor suppressor protein [28].
  • In an attempt to identify components downstream of MK2 in this pathway we analyzed several proteins which selectively interact with the ARE of GM-CSF mRNA [29].
  • MK2 interacts with polycomb complex protein edr2 [20]
  • MK2 interacts with and phosphorylates ER-associated ubiquitin conjugating enzyme- Ube2j1 at S184 [30]

Enzymatic interactions of MAPKAPK2


Regulatory relationships of MAPKAPK2


Other interactions of MAPKAPK2


Analytical, diagnostic and therapeutic context of MAPKAPK2


  1. Stimulation of "stress-regulated" mitogen-activated protein kinases (stress-activated protein kinases/c-Jun N-terminal kinases and p38-mitogen-activated protein kinases) in perfused rat hearts by oxidative and other stresses. Clerk, A., Fuller, S.J., Michael, A., Sugden, P.H. J. Biol. Chem. (1998) [Pubmed]
  2. MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer. Xu, L., Chen, S., Bergan, R.C. Oncogene (2006) [Pubmed]
  3. Doxycycline induces caspase-dependent apoptosis in human pancreatic cancer cells. Mouratidis, P.X., Colston, K.W., Dalgleish, A.G. Int. J. Cancer (2007) [Pubmed]
  4. Overexpression of glia maturation factor (GMF) in PC12 pheochromocytoma cells activates p38 MAP kinase, MAPKAP kinase-2, and tyrosine hydroxylase. Zaheer, A., Lim, R. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  5. Cytoskeletal changes in hypoxic pulmonary endothelial cells are dependent on MAPK-activated protein kinase MK2. Kayyali, U.S., Pennella, C.M., Trujillo, C., Villa, O., Gaestel, M., Hassoun, P.M. J. Biol. Chem. (2002) [Pubmed]
  6. MAPKAP kinase 2-deficiency prevents neurons from cell death by reducing neuroinflammation--relevance in a mouse model of Parkinson's disease. Thomas, T., Timmer, M., Cesnulevicius, K., Hitti, E., Kotlyarov, A., Gaestel, M. J. Neurochem. (2008) [Pubmed]
  7. A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Rouse, J., Cohen, P., Trigon, S., Morange, M., Alonso-Llamazares, A., Zamanillo, D., Hunt, T., Nebreda, A.R. Cell (1994) [Pubmed]
  8. Cdc25: mechanisms of checkpoint inhibition and recovery. Karlsson-Rosenthal, C., Millar, J.B. Trends Cell Biol. (2006) [Pubmed]
  9. MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation. Manke, I.A., Nguyen, A., Lim, D., Stewart, M.Q., Elia, A.E., Yaffe, M.B. Mol. Cell (2005) [Pubmed]
  10. The MAPK-activated kinase Rsk controls an acute Toll-like receptor signaling response in dendritic cells and is activated through two distinct pathways. Zaru, R., Ronkina, N., Gaestel, M., Arthur, J.S., Watts, C. Nat. Immunol. (2007) [Pubmed]
  11. Damage-induced DNA replication stalling relies on MAPK-activated protein kinase 2 activity. Köpper, F., Bierwirth, C., Schön, M., Kunze, M., Elvers, I., Kranz, D., Saini, P., Menon, M.B., Walter, D., Sørensen, C.S., Gaestel, M., Helleday, T., Schön, M.P., Dobbelstein, M. Proc. Natl. Acad. Sci. U. S. A. (2013) [Pubmed]
  12. 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. (2015) [Pubmed]
  13. Ischemic preconditioning triggers tyrosine kinase signaling: a potential role for MAPKAP kinase 2. Maulik, N., Yoshida, T., Zu, Y.L., Sato, M., Banerjee, A., Das, D.K. Am. J. Physiol. (1998) [Pubmed]
  14. MAPKAP kinase 2-deficient mice are resistant to collagen-induced arthritis. Hegen, M., Gaestel, M., Nickerson-Nutter, C.L., Lin, L.L., Telliez, J.B. J. Immunol. (2006) [Pubmed]
  15. Proteomic identification of 14-3-3zeta as a mitogen-activated protein kinase-activated protein kinase 2 substrate: role in dimer formation and ligand binding. Powell, D.W., Rane, M.J., Joughin, B.A., Kalmukova, R., Hong, J.H., Tidor, B., Dean, W.L., Pierce, W.M., Klein, J.B., Yaffe, M.B., McLeish, K.R. Mol. Cell. Biol. (2003) [Pubmed]
  16. 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, L.L., Fitzgibbon, M.J., Hayakawa, K., Ter Haar, E., Behrens, A.E., Fulghum, J.R., Lippke, J.A. J. Biol. Chem. (2002) [Pubmed]
  17. MAPKAP kinase-2 is a primary response gene induced by depolarization in PC12 cells and in brain. Vician, L.J., Xu, G., Liu, W., Feldman, J.D., Machado, H.B., Herschman, H.R. J. Neurosci. Res. (2004) [Pubmed]
  18. 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. Winzen, R., Kracht, M., Ritter, B., Wilhelm, A., Chen, C.Y., Shyu, A.B., Müller, M., Gaestel, M., Resch, K., Holtmann, H. EMBO J. (1999) [Pubmed]
  19. Rac1-MKK3-p38-MAPKAPK2 pathway promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells. Han, Q., Leng, J., Bian, D., Mahanivong, C., Carpenter, K.A., Pan, Z.K., Han, J., Huang, S. J. Biol. Chem. (2002) [Pubmed]
  20. MAPKAP kinase MK2 maintains self-renewal capacity of haematopoietic stem cells. Schwermann, J., Rathinam, C., Schubert, M., Schumacher, S., Noyan, F., Koseki, H., Kotlyarov, A., Klein, C., Gaestel, M. EMBO. J. (2009) [Pubmed]
  21. Identification of the p16-Arc subunit of the Arp 2/3 complex as a substrate of MAPK-activated protein kinase 2 by proteomic analysis. Singh, S., Powell, D.W., Rane, M.J., Millard, T.H., Trent, J.O., Pierce, W.M., Klein, J.B., Machesky, L.M., McLeish, K.R. J. Biol. Chem. (2003) [Pubmed]
  22. Sensitized mast cells migrate toward the antigen: a response regulated by p38 mitogen-activated protein kinase and Rho-associated coiled-coil-forming protein kinase. Ishizuka, T., Okajima, F., Ishiwara, M., Iizuka, K., Ichimonji, I., Kawata, T., Tsukagoshi, H., Dobashi, K., Nakazawa, T., Mori, M. J. Immunol. (2001) [Pubmed]
  23. Decreased p38 MAPK activity in end-stage failing human myocardium: p38 MAPK alpha is the predominant isoform expressed in human heart. Lemke, L.E., Bloem, L.J., Fouts, R., Esterman, M., Sandusky, G., Vlahos, C.J. J. Mol. Cell. Cardiol. (2001) [Pubmed]
  24. MEK kinase 3 directly activates MKK6 and MKK7, specific activators of the p38 and c-Jun NH2-terminal kinases. Deacon, K., Blank, J.L. J. Biol. Chem. (1999) [Pubmed]
  25. Phosphorylation of HSF1 by MAPK-activated protein kinase 2 on serine 121, inhibits transcriptional activity and promotes HSP90 binding. Wang, X., Khaleque, M.A., Zhao, M.J., Zhong, R., Gaestel, M., Calderwood, S.K. J. Biol. Chem. (2006) [Pubmed]
  26. SB202190-Induced Cell Type-Specific Vacuole Formation and Defective Autophagy Do Not Depend on p38 MAP Kinase Inhibition. Menon, M.B., Kotlyarov, A., Gaestel, M. PLoS. One. (2011) [Pubmed]
  27. The p38/reactivating kinase mitogen-activated protein kinase cascade mediates the activation of the transcription factor insulin upstream factor 1 and insulin gene transcription by high glucose in pancreatic beta-cells. Macfarlane, W.M., Smith, S.B., James, R.F., Clifton, A.D., Doza, Y.N., Cohen, P., Docherty, K. J. Biol. Chem. (1997) [Pubmed]
  28. The p38 and MK2 kinase cascade phosphorylates tuberin, the tuberous sclerosis 2 gene product, and enhances its interaction with 14-3-3. Li, Y., Inoki, K., Vacratsis, P., Guan, K.L. J. Biol. Chem. (2003) [Pubmed]
  29. Affinity purification of ARE-binding proteins identifies polyA-binding protein 1 as a potential substrate in MK2-induced mRNA stabilization. Bollig, F., Winzen, R., Gaestel, M., Kostka, S., Resch, K., Holtmann, H. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  30. Endoplasmic reticulum-associated ubiquitin-conjugating enzyme Ube2j1 is a novel substrate of MK2 (MAPKAP kinase-2) involved in MK2-mediated TNFα production. Menon, M.B., Tiedje, C., Lafera, J., Ronkina, N., Konen, T., Kotlyarov, A., Gaestel, M. Biochem. J. (2013) [Pubmed]
  31. Ischemic preconditioning: from adenosine receptor to KATP channel. Cohen, M.V., Baines, C.P., Downey, J.M. Annu. Rev. Physiol. (2000) [Pubmed]
  32. Activation of MAP kinase-activated protein kinase 2 in human neutrophils after phorbol ester or fMLP peptide stimulation. Zu, Y.L., Ai, Y., Gilchrist, A., Labadia, M.E., Sha'afi, R.I., Huang, C.K. Blood (1996) [Pubmed]
  33. Stress-induced phosphorylation of STAT1 at Ser727 requires p38 mitogen-activated protein kinase whereas IFN-gamma uses a different signaling pathway. Kovarik, P., Stoiber, D., Eyers, P.A., Menghini, R., Neininger, A., Gaestel, M., Cohen, P., Decker, T. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  34. p38 MAP kinase and MAPKAP kinases MK2/3 cooperatively phosphorylate epithelial keratins. Menon, M.B., Schwermann, J., Singh, A.K., Franz-Wachtel, M., Pabst, O., Seidler, U., Omary, M.B., Kotlyarov, A., Gaestel, M. J. Biol. Chem. (2010) [Pubmed]
  35. Stress induced gene expression: a direct role for MAPKAP kinases in transcriptional activation of immediate early genes. Ronkina, N., Menon, M.B., Schwermann, J., Arthur, J.S., Legault, H., Telliez, J.B., Kayyali, U.S., Nebreda, A.R., Kotlyarov, A., Gaestel, M. Nucleic. Acids. Res. (2011) [Pubmed]
  36. MK2 SUMOylation regulates actin filament remodeling and subsequent migration in endothelial cells by inhibiting MK2 kinase and HSP27 phosphorylation. Chang, E., Heo, K.S., Woo, C.H., Lee, H., Le, N.T., Thomas, T.N., Fujiwara, K., Abe, J. Blood. (2011) [Pubmed]
  37. p38MAPK/MK2-mediated phosphorylation of RBM7 regulates the human nuclear exosome targeting complex. Tiedje, C., Lubas, M., Tehrani, M., Menon, M.B., Ronkina, N., Rousseau, S., Cohen, P., Kotlyarov, A., Gaestel, M. RNA. (2015) [Pubmed]
  38. A quantitative 14-3-3 interaction screen connects the nuclear exosome targeting complex to the DNA damage response. Blasius, M., Wagner, S.A., Choudhary, C., Bartek, J., Jackson, S.P. Genes. Dev. (2014) [Pubmed]
  39. Inhibition of SAPK2a/p38 prevents hnRNP A0 phosphorylation by MAPKAP-K2 and its interaction with cytokine mRNAs. Rousseau, S., Morrice, N., Peggie, M., Campbell, D.G., Gaestel, M., Cohen, P. EMBO. J. (2002) [Pubmed]
  40. P66(ShcA) interacts with MAPKAP kinase 2 and regulates its activity. Yannoni, Y.M., Gaestel, M., Lin, L.L. FEBS Lett. (2004) [Pubmed]
  41. Protein expression of TNF-alpha in psoriatic skin is regulated at a posttranscriptional level by MAPK-activated protein kinase 2. Johansen, C., Funding, A.T., Otkjaer, K., Kragballe, K., Jensen, U.B., Madsen, M., Binderup, L., Skak-Nielsen, T., Fjording, M.S., Iversen, L. J. Immunol. (2006) [Pubmed]
  42. MAPKAPK-2-mediated LIM-kinase activation is critical for VEGF-induced actin remodeling and cell migration. Kobayashi, M., Nishita, M., Mishima, T., Ohashi, K., Mizuno, K. EMBO J. (2006) [Pubmed]
  43. Cross-regulation of cytokine signalling: pro-inflammatory cytokines restrict IL-6 signalling through receptor internalisation and degradation. Radtke, S., Wüller, S., Yang, X.P., Lippok, B.E., Mütze, B., Mais, C., de Leur, H.S., Bode, J.G., Gaestel, M., Heinrich, P.C., Behrmann, I., Schaper, F., Hermanns, H.M. J. Cell. Sci. (2010) [Pubmed]
  44. Retaining of the assembly capability of vimentin phosphorylated by mitogen-activated protein kinase-activated protein kinase-2. Cheng, T.J., Tseng, Y.F., Chang, W.M., Chang, M.D., Lai, Y.K. J. Cell. Biochem. (2003) [Pubmed]
  45. Identification of MAPKAP kinase 2 as a major enzyme responsible for the phosphorylation of the small mammalian heat shock proteins. Stokoe, D., Engel, K., Campbell, D.G., Cohen, P., Gaestel, M. FEBS. Lett. (1992) [Pubmed]
  46. Phosphorylation of alphaB-crystallin in mitotic cells and identification of enzymatic activities responsible for phosphorylation. Kato, K., Ito, H., Kamei, K., Inaguma, Y., Iwamoto, I., Saga, S. J. Biol. Chem. (1998) [Pubmed]
  47. The phosphorylation of CapZ-interacting protein (CapZIP) by stress-activated protein kinases triggers its dissociation from CapZ. Eyers, C.E., McNeill, H., Knebel, A., Morrice, N., Arthur, S.J., Cuenda, A., Cohen, P. Biochem. J. (2005) [Pubmed]
  48. LSP1 is the major substrate for mitogen-activated protein kinase-activated protein kinase 2 in human neutrophils. Huang, C.K., Zhan, L., Ai, Y., Jongstra, J. J. Biol. Chem. (1997) [Pubmed]
  49. p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Reinhardt, H.C., Aslanian, A.S., Lees, J.A., Yaffe, M.B. Cancer. Cell (2007) [Pubmed]
  50. The p38/MK2-driven exchange between tristetraprolin and HuR regulates AU-rich element-dependent translation. Tiedje, C., Ronkina, N., Tehrani, M., Dhamija, S., Laass, K., Holtmann, H., Kotlyarov, A., Gaestel, M. PLoS. Genet. (2012) [Pubmed]
  51. Serine/Threonine kinases 3pK and MAPK-activated protein kinase 2 interact with the basic helix-loop-helix transcription factor E47 and repress its transcriptional activity. Neufeld, B., Grosse-Wilde, A., Hoffmeyer, A., Jordan, B.W., Chen, P., Dinev, D., Ludwig, S., Rapp, U.R. J. Biol. Chem. (2000) [Pubmed]
  52. Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). Werz, O., Szellas, D., Steinhilber, D., Rådmark, O. J. Biol. Chem. (2002) [Pubmed]
  53. Proteomic identification of Bcl2-associated athanogene 2 as a novel MAPK-activated protein kinase 2 substrate. Ueda, K., Kosako, H., Fukui, Y., Hattori, S. J. Biol. Chem. (2004) [Pubmed]
  54. Examination of the kinetic mechanism of mitogen-activated protein kinase activated protein kinase-2. Schindler, J.F., Godbey, A., Hood, W.F., Bolten, S.L., Broadus, R.M., Kasten, T.P., Cassely, A.J., Hirsch, J.L., Merwood, M.A., Nagy, M.A., Fok, K.F., Saabye, M.J., Morgan, H.M., Compton, R.P., Mourey, R.J., Wittwer, A.J., Monahan, J.B. Biochim. Biophys. Acta (2002) [Pubmed]
  55. The substrate specificity and structure of mitogen-activated protein (MAP) kinase-activated protein kinase-2. Stokoe, D., Caudwell, B., Cohen, P.T., Cohen, P. Biochem. J. (1993) [Pubmed]
  56. Two distinct forms of MAPKAP kinase-2 in adult cardiac ventricular myocytes. Chevalier, D., Allen, B.G. Biochemistry (2000) [Pubmed]
  57. The primary structure of a human MAP kinase activated protein kinase 2. Zu, Y.L., Wu, F., Gilchrist, A., Ai, Y., Labadia, M.E., Huang, C.K. Biochem. Biophys. Res. Commun. (1994) [Pubmed]
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