Structure and function of MK5/PRAK: the loner among the mitogen-activated protein kinase-activated protein kinases

References

Aberg, E., Perander, M., Johansen, B., Julien, C., Meloche, S., Keyse, S.M., and Seternes, O.M. (2006). Regulation of MAPK-activated protein kinase 5 activity and subcellular localization by the atypical MAPK ERK4/MAPK4. J. Biol. Chem. 281, 35499–35510.10.1074/jbc.M606225200Search in Google Scholar

Aberg, E., Torgersen, K.M., Johansen, B., Keyse, S.M., Perander, M., and Seternes, O.M. (2009). Docking of PRAK/MK5 to the atypical MAPKs ERK3 and ERK4 defines a novel MAPK interaction motif. J. Biol. Chem. 284, 19392–19401.10.1074/jbc.M109.023283Search in Google Scholar

Andrews, M.J., Clase, J.A., Bar, G., Tricarico, G., Edwards, P.J., Brys, R., Chambers, M., Schmidt, W., MacLeod, A., Hirst, K., et al. (2012). Discovery of a series of imidazopyrazine small molecule inhibitors of the kinase MAPKAPK5 that shows activity using in vitro and in vivo models of rheumatoid arthritis. Bioorg. Med. Chem. Lett. 22, 2266–2270.10.1016/j.bmcl.2012.01.077Search in Google Scholar

Anwar, A., Hosoya, T., Leong, K.M., Onogi, H., Okuno, Y., Hiramatsu, T., Koyama, H., Suzuki, M., Hagiwara, M., and Garcia-Bianco, M.A. (2011). The kinase inhibitor SFV785 dislocates Dengue virus envelope protein from the replication complex and blocks virus assembly. PLoS One 6, e23246.10.1371/journal.pone.0023246Search in Google Scholar

Bain, J., McLauchlan, H., Elliot, M., and Cohen, P. (2003). The specificities of protein kinase inhibitors: an update. Biochem. J. 371, 199–204.10.1042/bj20021535Search in Google Scholar

Beites, C.L., Xie, H., Bowser, R., and Trimble, W.S. (1999). The septin CD Crel-1 binds syntaxin and inhibits exocytosis. Nat. Neurosci. 2, 434–439.10.1038/8100Search in Google Scholar

Beites, C.L., Peng, X.R., and Trimble, W.S. (2001). Expression and analysis of properties of septin CDCrel-1 in exocytosis. Methods Enzymol. 329, 499–510.10.1016/S0076-6879(01)29111-3Search in Google Scholar

Beites, C.L., Campbell, K.A., and Trimble, W.S. (2005). The septin Sept5/CDCrel-1 competes with alpha-SNAP for binding to the SNARE complex. Biochem. J. 385, 347–353.10.1042/BJ20041090Search in Google Scholar PubMed PubMed Central

Boivin, B., Khairallah, M., Cartier, R., and Allen, B.G. (2012). Characterization of hsp27 kinases activated by elevated aortic pressure in heart. Mol. Cell. Biochem. 371, 31–42.10.1007/s11010-012-1420-xSearch in Google Scholar PubMed PubMed Central

Brand, F., Schumacher, S., Kant, S., Menon, M.B., Simon, R., Turgeon, B., Britsch, S., Meloche, S., Gaestel, M., and Kotlyarov, A. (2012). The extracellular signal-regulated kinase 3 (mitogen-activated protein kinase 6 [MAPK6])-MAPK-activated protein kinase 5 signaling complex regulates function and dendrite morphology. Mol. Cell. Biol. 32, 2467–2478.10.1128/MCB.06633-11Search in Google Scholar PubMed PubMed Central

Cargnello, M. and Roux, P.P. (2011). Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol. Mol. Biol. Rev. 75, 50–83.10.1128/MMBR.00031-10Search in Google Scholar PubMed PubMed Central

Chen, G., Hitomi, M., Han, J., and Stacey, D.W. (2000). The p38 pathway provides negative feedback for Ras proliferative signaling. J. Biol. Chem. 275, 38973–80.10.1074/jbc.M002856200Search in Google Scholar PubMed

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

Choi, J.H., Choi, D.K., Sohn, K.C., Kwak, S.S., Suk, J., Lim, J.S., Shin, I., Kim, S.W., Lee, J.H., and Joe, C.O. (2012). Absence of a human DnaJ protein hTid-1s correlates with aberrant actin cytoskeleton organization in lesional psoriatic skin. J. Biol. Chem. 287, 25954–25963.10.1074/jbc.M111.313809Search in Google Scholar PubMed PubMed Central

Colwill, K., Renewable Protein Binder Working Group, and Gräslund, S. (2011). A roadmap to generate renewable protein binders to the human proteome. Nat. Methods 8, 551–558.10.1038/nmeth.1607Search in Google Scholar PubMed

Coulombe, P., Rodier, G., Pelletier, S., Pellerin, J., and Meloche, S. (2003). Rapid turnover of extracellular signal-regulated kinase 3 by the ubiquitin-proteasome pathway defines a novel paradigm of mitogen-activated protein kinase regulation during cellular differentiation. Mol. Cell. Biol. 23, 4542–4558.10.1128/MCB.23.13.4542-4558.2003Search in Google Scholar PubMed PubMed Central

Dahlman, K.B., Parker, J.S., Shamu, T., Hieronymus, H., Chapinski, C., Carver, B., Chang, K., Hannon, G.J., and Sawyers, C.L. (2012). Modulators of prostate cancer cell proliferation and viability identified by short-hairpin RNA library screening. PLoS One 7, e34414.10.1371/journal.pone.0034414Search in Google Scholar PubMed PubMed Central

Datta, S., Hoenerhoff, M.J., Bommi, P., Sainger, R., Guo, W.J., Dimri, M., Band, H., Band, V., Green, J.E., and Goberdhan, P.D. (2007). Bmi-1 cooperates with H-Ras to transform human mammary epithelial cells via dysregulation of multiple growth regulatory pathways. Cancer Res. 67, 10286–10295.10.1158/0008-5472.CAN-07-1636Search in Google Scholar PubMed PubMed Central

De La Mota-Peynado, A., Chernoff, J., and Beeser, A. (2011). Identification of the atypical MAPK Erk3 as a novel substrate for p21-activated kinase (Pak) activity. J. Biol. Chem. 286, 13603–13611.10.1074/jbc.M110.181743Search in Google Scholar PubMed PubMed Central

Déléris, P., Rousseau, J., Coulombe, P., Rodier, G., Tanguay, P.L., and Meloche, S. (2008). Activation loop phosphorylation of the atypical MAP kinases ERK3 and ERK4 is required for binding, activation and cytoplasmic relocalization of MK5. J. Cell. Physiol. 217, 778–788.10.1002/jcp.21560Search in Google Scholar PubMed

Déléris, P., Trost, M., Topisirovic, I., Tanguay, P.L., Borden, K.L., Thibault, P., and Meloche, S. (2010). Activation loop phosphorylation of ERK3/ERK4 by group I PAKs defines a novel PAK-ERK3/4-MK5 signaling pathway. J. Biol. Chem. 286, 6470–6478.10.1074/jbc.M110.181529Search in Google Scholar PubMed PubMed Central

Del Rincón, S.V., Rogers, J., Widschwendter, M., Sun, D., Sieburg, H.B., and Spruck, C. (2010). Development and validation of a method form profiling post-translational modification activities using protein microarrays. PLoS One 5, e11332.Search in Google Scholar

Dent, J., Kato, K., Peng, X.R., Martinez, C., Cattaneo, M., Poujol, C., Nurden, P., Nurden, A., Trimble, W.S., and Ware, J. (2002). A prototypic platelet septin and its participation in secretion. Proc. Natl. Acad. Sci. USA 99, 3064–3069.10.1073/pnas.052715199Search in Google Scholar PubMed PubMed Central

Dindot, S.V., Antalffy, B.A., Bhattacharjee, M.B., and Beaudet, A.L. (2008). The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology. Hum. Mol. Genet. 17, 111–118.10.1093/hmg/ddm288Search in Google Scholar PubMed

Dingar, D., Benoit, M.J., Mamarbachi, A.M., Villeneuve, L.R., Gillis, M.A., Grandy, S., Gaestel, M., Fiset, C., and Allen, B.G. (2010). Characterization of the expression and regulation of MK5 in the murine ventricular myocardium. Cell. Signal. 22, 1063–1075.10.1016/j.cellsig.2010.02.009Search in Google Scholar PubMed PubMed Central

Dissanayake, K., Toth, T., Blakey, J., Olsson, O., Campbell, D.G., Prescott, A.R., and MacKintosh, C. (2011). ERK/p90(RSK)/14-3-3 signalling has an impact on expression of PEA3 Ets transcription factors via the transcriptional repressor capicúa. Biochem. J. 433, 515–525.10.1042/BJ20101562Search in Google Scholar PubMed PubMed Central

Ewen, K., Jackson, A., Wilhelm, D., and Koopman, P. (2010). A male-specific role for p38 mitogen-activated protein kinase in germ cell sex differentiation in mice. Biol. Reprod. 83, 1005–1014.10.1095/biolreprod.110.086801Search in Google Scholar PubMed

Folmer, F., Blasius, R., Morceau, F., Tabudravu, J., Dicato, M., Jaspars, M., and Diederich, M. (2006). Inhibition of TNFα-induced activation of nuclear factor κB by kava (Piper methysticum) derivatives. Biochem. Pharmacol. 71, 1206–1218.10.1016/j.bcp.2005.12.032Search 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

Geiss-Friedlander, R. and Melchior, F. (2007). Concepts in sumoylation: a decade on. Nat. Rev. Mol. Cell. Biol. 8, 947–956.10.1038/nrm2293Search in Google Scholar PubMed

Gerits, N., Mikalsen, T., Kostenko, S., Shiryaev, A., Johannessen, M., and Moens, U. (2007a) Modularion of F-actin rearrangement by the cyclic AMP/cAMP-dependent protein kinase (PKA) pathway is mediated by MAPK-activated protein kinase 5 and requires PKA-induced nuclear export of MK5. J. Biol. Chem. 282, 37232–27243.10.1074/jbc.M704873200Search in Google Scholar PubMed

Gerits, N., Van Belle, W., and Moens, U. (2007b). Transgenic mice expressing constitutive active MAPKAPK5 display gender-dependent differences in exploration and activity. Behav. Brain Funct. 3, 58.10.1186/1744-9081-3-58Search in Google Scholar PubMed PubMed Central

Gerits, N., Shiryaev, A., Kostenko, S., Klenow, H., Shiryaeva, O., Johannessen, M., and Moens, U. (2009). The transcriptional regulation and cell-specific expression of the MAPK-activated protein kinase MK5. Cell. Mol. Biol. Lett. 14, 548–574.10.2478/s11658-009-0020-6Search in Google Scholar PubMed PubMed Central

Gong, X., Ming, X., Deng, P., and Jiang, Y. (2010). Mechanisms regulating the nuclear translocation of p38 MAP kinase. J. Cell. Biochem. 110, 1420–1429.10.1002/jcb.22675Search in Google Scholar PubMed

Hansen, C.A., Bartek, J., and Jensen, S. (2008). A functional link between the human cell cycle-regulatory phosphatase Cdc14A and the atypical mitogen-activated kinase Erk3. Cell Cycle 7, 325–334.10.4161/cc.7.3.5354Search in Google Scholar PubMed

Hefner, Y., Borsch-Haubold, A.G., Murakami, M., Wilde, J.I., Pasquet, S., Schieltz, D., Ghomashchi, F., Yates, J.R. 3rd, Armstrong, C.G., Paterson, A., et al. (2000). Serine 727 phosphorylation and activation of cytosolic phospholipase A2 by MNK1-related protein kinase. J. Biol. Chem. 275, 37542–37551.10.1074/jbc.M003395200Search 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

Holt, R., Sykes, N.H., Conceição, I.C., Cazier, J.B., Anney, R.J., Oliveira, G., Gallagher, L., Vicente, A., Monaco, A.P., and Pagnamenta, A.T. (2012). CNVs leading to fusion transcripts in individuals with autism spectrum disorder. Eur. J. Hum. Genet. 20, 1141–1147.10.1038/ejhg.2012.73Search in Google Scholar PubMed PubMed Central

Hu, Y., Xu, H., Li, Z., Zheng, X., Jia, X., Nie, Q., and Zhang, X. (2013). Comparison of the genome-wide DNA methylation profiles between fast-growing and slow-growing broilers. PLoS One 8, e56411.10.1371/journal.pone.0056411Search in Google Scholar PubMed PubMed Central

Ito, H., Atsuzawa, K., Morishita, R., Usuda, N., Sudo, K., Iwamoto, I., Mizutani, K., Katoh-Semba, R., Nozawa, Y., Asano, T., et al. (2009). Sept8 controls the binding of vesicle-associated membrane protein 2 to synaptophysin. J. Neurochem. 108, 867–880.10.1111/j.1471-4159.2008.05849.xSearch in Google Scholar PubMed

Jenö, P., Ballou L.M., Novak-Hofer, I., and Thomas, G. (1988). Identification and characterization of a mitogen-activated S6 kinase. Proc. Natl. Acad. Sci. USA 85, 406–410.10.1073/pnas.85.2.406Search in Google Scholar PubMed PubMed Central

Julien, C., Coulombe, P., and Meloche, S. (2003). Nuclear export of ERK3 by a CRM1-dependent mechanism regulates its inhibitory action on cell cycle progression. J. Biol. Chem. 278, 42615–42624.10.1074/jbc.M302724200Search in Google Scholar PubMed

Kant, S., Schumacher, S., Singh, M.K., Kispert, A., Kotlyarov, A., and Gaestel, M. (2006). Characterization of the atypical MAPK ERK4 and its activation of the MAPK-activated protein kinase MK5. J. Biol. Chem. 281, 35511–35519.10.1074/jbc.M606693200Search in Google Scholar PubMed

Knebel, A., Haydon, C.E., Morrice, N., and Cohen, P. (2002). Stress-induced regulation of eukaryotic elongation factor 2 kinase by SB203580-sensitive and -insensitive pathways. Biochem. J. 367, 525–532.10.1042/bj20020916Search in Google Scholar

Koh, G.C., Schreiber, M.F., Bautista, R., Maude, R.R., Dunachie, S., Limmathurotsakul, D., Day, N.P., Dougan, G., and Peacock, S.J. (2013). Host responses to melioidosis and tuberculosis are both dominated by interferon-mediated signalling. PLoS One 8, e54961.10.1371/journal.pone.0054961Search in Google Scholar PubMed PubMed Central

Kostenko, S. and Moens, U. (2009). Heat shock protein 27 phosphorylation: kinases, phosphatases, functions and pathology. Cell. Mol. Life Sci. 66, 3289–3307.10.1007/s00018-009-0086-3Search in Google Scholar PubMed

Kostenko, S. and Moens, U. (2012). HSP27 phosphorylation patterns and consequences. In Cellular trafficking of cell stress proteins in health and disease. Heat shock proteins, Vol. 6, B. Henderson and A.G. Pockley, eds. (Cham, Switzerland: Springer International Publishing AG), pp. 43–74.Search in Google Scholar

Kostenko, S., Johannessen, M., and Moens, U. (2009). PKA-induced F-actin rearrangement requires phosphorylation of Hsp27 by the MAPKAP kinase MK5. Cell. Signal. 21, 712–718.10.1016/j.cellsig.2009.01.009Search in Google Scholar PubMed

Kostenko S, Dumitriu G, Lægreid K.J., and Moens U. (2011a). Physiological roles of mitogen-activated-protein-kinase-activated p38-regulated/activated protein kinase. World J. Biol. Chem. 2, 73–89.10.4331/wjbc.v2.i5.73Search in Google Scholar PubMed PubMed Central

Kostenko, S., Shiryaev, A., Gerits, N., Dumitriu, G., Klenow, H., Johannessen, M., and Moens, U. (2011b). Serine residue 115 of MAPK-activated protein kinase MK5 is crucial for its PKA-regulated nuclear export and biological function. Cell. Mol. Life Sci. 68, 847–862.10.1007/s00018-010-0496-2Search in Google Scholar PubMed PubMed Central

Kostenko, S., Khan, M.T., Sylte, I., and Moens, U. (2011c). The diterpenoid alkaloid noroxoaconitine is a Mapkap kinase 5 (MK5/PRAK) inhibitor. Cell. Mol. Life Sci. 68, 289–301.10.1007/s00018-010-0452-1Search in Google Scholar PubMed PubMed Central

Kostenko, S., Dumitriu, G., and Moens, U. (2012). Tumour promoting and suppressing roles of the atypical MAP kinase signalling pathway ERK3/4-MK5. J. Mol. Signal. 7, 9.10.1186/1750-2187-7-9Search in Google Scholar PubMed PubMed Central

Kozak, M. (1996). Interpreting cDNA sequences: some insights from studies on translation. Mamm. Genome 7, 563–574.10.1007/s003359900171Search in Google Scholar PubMed

Kress, T.R., Cannell, I.G., Brenkman, A.B., Samans, B., Gaestel, M., Toepman, P., Burgering, B.M., Bushell, M., Rosenwald, A., and Eilers, M. (2011). The MK5/PRAK kinase and Myc form a negative feedback loop that is disrupted during colorectal tumorigenesis. Mol. Cell 41, 445–457.10.1016/j.molcel.2011.01.023Search in Google Scholar PubMed

Kyriakis, J.M. and Avruch, J. (2012). Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol Rev. 92, 689–737.10.1152/physrev.00028.2011Search in Google Scholar PubMed

Li, Q., Zhang, N., Zhang, D., Wang, Y., Lin, T., Wang, Y., Zhou, H., Ye, Z., Zhang, F., Lin, S.C., et al. (2008). Determinants that control the distinct subcellular localization of the p38α-PRAK and the p38β-PRAK complexes. J. Biol. Chem. 283, 11014–11023.10.1074/jbc.M709682200Search in Google Scholar PubMed

Li, M., Liu, J., and Zhang, C. (2011). Evolutionary history of the vertebrate mitogen activated protein kinases family. PLoS One 6, e26999.10.1371/journal.pone.0026999Search in Google Scholar PubMed PubMed Central

Lomelí, H. and Vázquez, M. (2011). Emerging roles of the SUMO pathway in development. Cell. Mol. Life Sci. 68, 4045–4064.10.1007/s00018-011-0792-5Search in Google Scholar PubMed

Ma, W., Xia, C., Ling, P., Qiu, M., Luo, Y., Tan, T.H., and Liu, M. (2001). Leukocyte-specific adaptor protein Grap2 interacts with hematopoietic progenitor kinase 1 (HPK1) to activate JNK signaling pathway in T lymphocytes. Oncogene 20, 1703–1714.10.1038/sj.onc.1204224Search in Google Scholar PubMed

Martinez-Noël, G., Galligan, J.T., Sowa, M.E., Arndt, V., Overton, T.M., Harper, J.W., and Howley, P.M. (2012). Identification and proteomic analysis of distinct UBE3A/E6AP protein complexes. Mol. Cell. Biol. 32, 3095–3106.10.1128/MCB.00201-12Search in Google Scholar PubMed PubMed Central

Marasa, B.S., Srikantan, S., Masuda, K., Abdelmohsen, K., Kuwano, Y., Yang, X., Martindale, J.L., Rinker-Schaeffer, C.W., and Gorospe, M. (2009). Increased MKK4 abundance with replicative senescence is linked to the joint reduction of multiple microRNAs. Sci. Signal. 2, ra69.10.1126/scisignal.2000442Search in Google Scholar PubMed PubMed Central

Mayya, V., Lundgren, D.H., Hwang, S.I., Rezaul, K., Wu, L., Eng, J.K., Rodionov, V., and Han, D.K. (2009). Quantitative phosphoproteomic analysis of T cell receptor signalling reveals system-wide modulation of protein-protein interactions. Sci. Signal. 2, ra46.10.1126/scisignal.2000007Search in Google Scholar PubMed

Meyer, N. and Penn, L.Z. (2008). Reflecting on 25 years with MYC. Nat. Rev. Cancer 8, 976–990.10.1038/nrc2231Search in Google Scholar PubMed

Moens, U., Shiryaev, A., and Dumitriu, G. (2010). Comment on “Increased MKK4 abundance with replicative senescence is linked to the joint reduction of multiple microRNAs”. Sci. Signal. 3, lc1; author reply lc2.Search in Google Scholar

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

Nagele, E., Han, M., Demarshall, C., Belinka, B., and Nagele, R. (2011). Diagnosis of Alzheimer’s disease based on disease-specific autoantibody profiles in human sera. PLoS One 6, e23112.10.1371/journal.pone.0023112Search in Google Scholar PubMed PubMed Central

Namour, F., Vanhoutte, F.P., Beetens, J., Blockhuis, S., De Weer, M., and Wigerinck, P. (2012). Pharmacokinetics, safety, and tolerability of GLPG0259, a mitogen-activated protein kinase-activated protein kinase 5 (MAPKAPK5) inhibitor, given as single and multiple doses to healthy male subjects. Drugs R D 12, 141–163.10.2165/11633120-000000000-00000Search in Google Scholar PubMed PubMed Central

Natale, D.R., Paliga, A.J., Beier, F., D’Souza, S.J., and Watson, A.J. (2004). P38 MAPK signalling during murine preimplantation development. Dev. Biol. 268, 76–88.10.1016/j.ydbio.2003.12.011Search in Google Scholar PubMed

Navarathna, D.H., Lionakis, M.S., Lizak, M.J., Munasinghe, J., Nickerson, K.W., and Roberts, D.D. (2012). Urea amidolyase (DUR1,2) contributes to virulence and kidney pathogenesis of Candida albicans. PLoS One 7, e48475.10.1371/journal.pone.0048475Search in Google Scholar PubMed PubMed Central

New, L., Jiang, Y., Zhao, M., Liu, K., Zhu, W., Flood, L.J., Kato, Y., Parry, G.C., and Han, J. (1998). PRAK, a novel protein kinase regulated by the p38 MAP kinase. EMBO J. 17, 3372–3384.10.1093/emboj/17.12.3372Search in Google Scholar PubMed PubMed Central

New, L., Jiang, Y., and Han, J. (2003). Regulation of PRAK subcellular location by p38 MAP kinases. Mol. Biol. Cell 14, 2603–2616.10.1091/mbc.e02-08-0538Search in Google Scholar PubMed PubMed Central

Ni, H., Wang, X.S., Diener, K., and Yao, Z. (1998). MAPKAPK5, a novel mitogen-activated protein kinase (MAPK)-activated protein kinase, is a substrate of the extracellular-regulated kinase (ERK) and p38 kinase. Biochem. Biophys. Res. Commun. 243, 492–496.10.1006/bbrc.1998.8135Search in Google Scholar PubMed

Notredame, C., Higgins, D.G., and Heringa, J. (2000). T-coffee: a novel method for multiple sequence alignments. J. Mol. Biol. 302, 205–217.10.1006/jmbi.2000.4042Search in Google Scholar PubMed

Oberman, F., Rand, K., Maizels, Y, Rubinstein, A.M., and Yisraeli, J.K. (2007). VICKZ proteins mediate cell migration via their RNA binding activity. RNA 13, 1558–1569.10.1261/rna.559507Search in Google Scholar PubMed PubMed Central

Pelech, S.L., Olwin, B.B., and Krebs, E.G. (1986). Fibroblast growth factor treatment of Swiss 3T3 cells activates a subunit S6 kinase that phosphorylates a synthetic peptide substrate. Proc. Natl. Acad. Sci. USA 83, 5968–5972.10.1073/pnas.83.16.5968Search in Google Scholar PubMed PubMed Central

Perander, M., Aberg, E., Johansen, B., Dreyer, B., Guldvik, I.J., Outzen, H. Keyse, S.M., and Seternes, O.M. (2008). The Ser(186) phosphoacceptor site within ERK4 is essential for its ability to interact with and activate PRAK/MK5. Biochem J. 411, 613–622.10.1042/BJ20071369Search in Google Scholar PubMed

Persaud, A., Alberts, P., Amsen, E.M., Xiong, X., Wasmuth, J., Saadon, Z., Fladd, C., Parkinson, J., and Rotin, D. (2009). Comparison of substrate specificity of the ubiquitin ligases Nedd4 and Nedd4-2 using proteome arrays. Mol. Syst. Biol. 5, 333.10.1038/msb.2009.85Search in Google Scholar PubMed PubMed Central

Poon, K.S.V. (2004). Bindings of p38 MAPK and PRAK to the large cytoplasmic loop of GLUT4. Thesis (M. Sc.), University of Toronto.Search in Google Scholar

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., et al. (2003). Proteomic identification of 14-3-3zeta as a mitogen-activated protein kinase-activated protein kinase 2 substrate: role in dimer formation and ligand binding. Mol. Cell. Biol. 23, 5376–5387.10.1128/MCB.23.15.5376-5387.2003Search in Google Scholar PubMed PubMed Central

Praefcke, G.J., Hofmann, K., and Dohmen, R.J. (2012). SUMO playing tag with ubiquitin. Trends Biochem. Sci 37, 23–31.10.1016/j.tibs.2011.09.002Search in Google Scholar PubMed

Ravikumar, B., Vacher, C., Berger, Z., Davies, J.E., Luo, S., Oroz, L.G., Scaravilli, F., Easton, D.F., Duden, R., O’Kane, C.J., et al. (2004). Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585–595.10.1038/ng1362Search in Google Scholar PubMed

Ray, L.B. and Sturgill, T.W. (1987). Rapid stimulation by insulin of a serine/threonine kinase in 3T3-L1 adipocytes that phosphorylates microtubule-associated protein 2 in vitro. Proc. Natl. Acad. Sci. USA 84, 1502–1506.10.1073/pnas.84.6.1502Search in Google Scholar PubMed PubMed Central

Rousseau, S., Morrice, N., Peggie, M., Campbell, D.G. Gaestel, M., and Cohen, P. (2002). Inhibition of SAPK2a/p38 prevents hnRNP A0 phosphorylation by MAPKAP-K2 and its interaction with cytokine mRNAs. EMBO J. 21, 6505–6514.10.1093/emboj/cdf639Search in Google Scholar PubMed PubMed Central

Schumacher, S., Laass, K., Kant, S., Shi, Y., Visel, A., Gruber, A.D., Kotlyarov, A., and Gaestel, M. (2004). Scaffolding by ERK3 regulates MK5 in development. EMBO J. 23, 4770–4779.10.1038/sj.emboj.7600467Search in Google Scholar PubMed PubMed Central

Seternes, O.M., Johansen, B., Hegge, B., Johannessen, M., Keyse, S.M., and Moens U. (2002). Both binding and activation of p38 mitogen-activated protein kinase (MAPK) play essential roles in regulation of the nucleocytoplasmic distribution of MAPK-activated protein kinase 5 by cellular stress. Mol. Cell. Biol. 22, 6931–6945.10.1128/MCB.22.20.6931-6945.2002Search in Google Scholar PubMed PubMed Central

Seternes, O.M., Mikalsen, T., Johansen, B., Michaelsen, E., Armstrong, C.G., Morrice, N.A., Turgeon, B., Meloche, S., Moens, U., and Keyse, S.M. (2004). Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway. EMBO J. 23, 4780–4791.10.1038/sj.emboj.7600489Search in Google Scholar PubMed PubMed Central

Shi, Y., Kotlyarov, A., Laas, K., Gruber, A.D., Butt, E., Marcus, K., Meyer, H.E., Friedrich, A., Volk, H.D., and Gaestel, M. (2003). Elimination of protein kinase MK5/PRAK activity by targeted homologous recombination. Mol. Cell. Biol. 23, 7732–7741.10.1128/MCB.23.21.7732-7741.2003Search in Google Scholar PubMed PubMed Central

Shiromizu, T., Adachi, J., Watanabe, S., Murakami, T., Kuga, T., Muraoka, S., and Tomonaga, T. (2013). Identification of missing proteins in the neXtProt Database and unregistered phosphopeptides in the phosphopeptides in the PhosphoSitePlus database as part of the chromosome-centric human proteome project. J. Proteome Res. 12, 2414–2421.10.1021/pr300825vSearch in Google Scholar PubMed

Shiryaev, A. and Moens, U. (2010). Mitogen-activated protein kinase p38 and MK2, MK3 and MK5: ménage à trois or ménage à quatre? Cell. Signal. 22, 1185–1192.10.1016/j.cellsig.2010.03.002Search in Google Scholar PubMed

Shiryaev, A., Dumitriu, G., and Moens, U. (2011). Distinct roles of MK2 and MK5 in cAMP/PKA- and stress/p38MAPK-induced heat shock protein 27 phosphorylation. J. Mol. Signal. 6, 4.10.1186/1750-2187-6-4Search in Google Scholar PubMed PubMed Central

Shiryaev, A., Kostenko, S., Dumitriu, G., and Moens, U. (2012). Septin 8 is an interaction partner and in vitro substrate of MK5. World J. Biol. Chem. 3, 98–109.10.4331/wjbc.v3.i5.98Search in Google Scholar PubMed PubMed Central

Sohal, D., Yeatts, A., Ye, K., Pellagatti, A., Zhou, L., Pahanish, P., Mo, Y., Bhagat, T., Mariadason, J., Boultwood, J., et al. (2008). Meta-analysis of microarray studies reveal a novel hematopoietic progenitor cell signature and demonstrates feasibility of inter-platform data integration. PLoS One 3, e2965.10.1371/journal.pone.0002965Search in Google Scholar PubMed PubMed Central

Srivastav, R.K., Schwede, S., Klaus, M., Schwermann, J., Gaestel, M., and Niedenthal, R. (2011). Monitoring protein-protein interactions in mammalian cells by trans-SUMOylation. Biochem. J. 438, 495–503.10.1042/BJ20110035Search in Google Scholar PubMed

Stöhr, N., Köhn, M., Lederer, M., Glass, M., Reinke, C., Singer, R.H., and Hüttelmaier, S. (2012) IGF2BP1 promotes cell migration by regulating MK5 and PTEN signaling. Genes Dev. 26, 176–189.10.1101/gad.177642.111Search in Google Scholar PubMed PubMed Central

Sun, P., Yoshizuka, N., New, L., Moser, B.A., Li, Y., Liao, R., Xie, C., Chen, J., Deng, Q., Yamout, M., et al. (2007). PRAK is essential for ras-induced senescence and tumor suppression. Cell 128, 295–308.10.1016/j.cell.2006.11.050Search in Google Scholar PubMed

Tak, H., Jang, E., Kim, S.B., Park, J., Sun, J., Yoon, Y.S., Ahn, J.K., Lee, J.H., and Joe, C.O. (2007). 14-3-3epsilon inhibits MK5-mediated cell migration by disrupting F-actin polymerization. Cell. Signal. 19, 2379–2387.10.1016/j.cellsig.2007.07.016Search in Google Scholar PubMed

Tamai, T., Yamaguchi, O., Hikoso, S., Takeda, T., Taneike, M., Oka, T., Oyabu, J., Murakawa, T., Nakayama, H., Uno, Y., et al. (2013). Ras homologue enriched in brain (Rheb)-dependent mTORC1 activation becomes indispensable for cardiac hypertrophic growth after early postnatal period. J. Biol. Chem. 288, 10176–10187.10.1074/jbc.M112.423640Search in Google Scholar PubMed PubMed Central

Tanguay, P.L., Rodier, G., and Meloche, S. (2010). C-terminal domain phosphorylation of ERK3 controlled by Cdk1 and Cdc14 regulates its stability in mitosis. Biochem. J. 428, 101–111.10.1042/BJ20091604Search in Google Scholar PubMed

Toska, K., Kleppe, R., Armstrong, C.G., Morrice, N.A., Cohen, P., and Haavik, J. (2002). Regulation of tyrosine hydroxylase by stress-activated protein kinases. J. Neurochem. 83, 775–783.10.1046/j.1471-4159.2002.01172.xSearch in Google Scholar PubMed

Trang, T., Beggs, S., Wan, X., and Salter, M.W. (2009). P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen activated protein kinase activation. J. Neurosci. 29, 3518–3528.10.1523/JNEUROSCI.5714-08.2009Search in Google Scholar PubMed PubMed Central

Van Buggenhout, G. and Fryns, J.P. (2009). Angelman syndrome (AS, MIM 105830). Eur. J. Hum. Genet. 17, 1367–1373.10.1038/ejhg.2009.67Search in Google Scholar PubMed PubMed Central

Van Belle, W., Gerits, N., Jakobse, n K., Brox, V., Van Ghelue, M., and Moens U. (2007). Intensity dependent confidence intervals on microarray measurements of differentially expressed genes: a case study of the effect of MK5, FKRP and TAF4 on the transcriptome. Gene Regul. Syst. Biol. 1, 57–72.Search in Google Scholar

Vainer, G., Vainer-Mosse, E., Pikarsky, A., Shenoy, S.M., Obermand, F., Yeffet, A., Singer, R.H., Pikarsky, E., and Yisraeli, J.K. (2008). A role for VICKZ proteins in the progression of colorectal carcinomas: regulating lamellipodia formation. J. Pathol. 215, 445–456.10.1002/path.2376Search in Google Scholar PubMed PubMed Central

Vikensaa, J., Hansen, T.V., Jonson, L., Borup, R., Wewer, U.M., Christiansen, J., and Nielsen, F.C. (2006). RNA-binding IMPs promote cell adhesion and invadopodia formation. EMBO J. 25, 1456–1468.10.1038/sj.emboj.7601039Search in Google Scholar PubMed PubMed Central

Wang, X., Li, W., Williams, M., Terada, N., Alessi, D.R., and Proud, C.G. (2001). Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J. 20, 4370–4379.10.1093/emboj/20.16.4370Search in Google Scholar PubMed PubMed Central

Wang, X., Chen, W., Li, X., Zhou, C., Deng, C., Lv, X., Fan, Y., Men, J., Liang, C., and Yu, X. (2012). Identification and molecular characterization of a novel signalling molecule 14-3-3 epsilin in Clonorchis sinensis excretory/secretory products. Parasitol. Res. 110, 1411–1420.10.1007/s00436-011-2642-7Search in Google Scholar PubMed

Weber, C., Schreiber, T.B., and Daub, H. (2012). Dual phosphoproteomics and chemical proteomics analysis of erlotinib and gefitinib interference in acute myeloid leukemia cells. J. Proteomics 75, 1343–1356.10.1016/j.jprot.2011.11.004Search in Google Scholar PubMed

Westhovens, R., Keyser, F.D., Rekalov, D., Nasonov, E.L., Beetens, J., Van der Aa, A., Wigerinck, P., Namour, F., Vanhoutte, F., and Durez, P. (2012). Oral administration of GLPG0259, an inhibitor of MAPKAPK5, a new target for the treatment of rheumatoid arthritis: a phase II, randomised, double-blind, placebo-controlled, multicentre trial. Ann. Rheum. Dis. 72, 741–744.10.1136/annrheumdis-2012-202221Search in Google Scholar PubMed

White, A., Pargellis, C.A., Studts, J.M., Werneburg, B.G., and Farmer, B.T. 2nd. (2007). Molecular basis of MAPK-activated protein kinase 2:p38 assembly. Proc. Natl. Acad. Sci. USA 104, 6353–6358.10.1073/pnas.0701679104Search in Google Scholar PubMed PubMed Central

Whitworth, H., Bhadel, S., Ivey, M., Conaway, M., Spencer, A., Hernan, R., Holemon, H., and Gioeli, D. (2012). Identification of kinases regulating prostate cancer cell growth using an RNAi phenotypic screen. PLoS One 7, e38950.10.1371/journal.pone.0038950Search in Google Scholar PubMed PubMed Central

Widmann, C., Gibson, S., Jarpe, M.B., and Johnson, G.L. (1999). Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol. Rev. 79, 143–180.10.1152/physrev.1999.79.1.143Search in Google Scholar PubMed

Winge, I., McKinney, J.A., Ying, M., D’Santos, C.S., Kleppe, R., Knappskog, P.M., and Haavik, J. (2008). Activation and stabilization of human tryptophan hydroxylase 2 by phosphorylation and 14-3-3 binding. Biochem. J. 410, 195–204.10.1042/BJ20071033Search in Google Scholar PubMed

Xie, J., Ponuwei, G.A., Moore, C.E., Willars, G.B., Tee, A.R., and Herbert, T.P. (2011). cAMP inhibits mammalian target of rapamycin complex-1 and -2 (mTORC1 and 2) by promoting complex dissociation and inhibiting mTOR kinase activity. Cell. Signal. 23, 1927–1935.10.1016/j.cellsig.2011.06.025Search in Google Scholar PubMed PubMed Central

Yan, C., Ding, X., Dasgupta, N., Wu, L., and Du, H. (2012). Gene profile of myeloid-derived suppressive cells from the bone marrow of lysosomal acid lipase knock-out mice. PLoS One 7, e30701.10.1371/journal.pone.0030701Search in Google Scholar PubMed PubMed Central

Yoshizuka, N., Chen, R.M., Xu, Z., Liao, R., Hong, L., Hi, W.Y., Yu, G., Han, J., Chen, L., and Sun, P. (2012a). A novel function of p38-regulated/activated kinase in endothelial cell migration and tumor angiogenesis. Mol. Cell. Biol. 32, 606–618.10.1128/MCB.06301-11Search in Google Scholar PubMed PubMed Central

Yoshizuka, N., Lai, M., Liao, R., Cook, R., Xiao, C., Han, J., and Sun, P. (2012b). PRAK suppresses oncogenic ras-induced hematopoietic cancer development by antagonizing the JNK pathway. Mol. Cancer Res. 10, 810–820.10.1158/1541-7786.MCR-11-0576Search in Google Scholar PubMed PubMed Central

Zhao, X. and Guan, J.L. (2011). Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis. Adv. Drug Deliv. Rev. 63, 610–615.10.1016/j.addr.2010.11.001Search in Google Scholar PubMed PubMed Central

Zheng, M., Wang, Y.H., Wu, X.N., Wu, S.Q., Lu, B.J., Dong, M.Q., Zhang, H., Sun, P., Lin, S.C., Guan, K.L., et al. (2011). Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1. Nat. Cell Biol. 13, 263–272.10.1038/ncb2168Search in Google Scholar PubMed PubMed Central

Zhou, J., Wan, B., Liu, X.M., Li, R., Wang, Y., and Yu, L. (2012). MK5 is degraded in response to doxorubicin and negatively regulates doxorubicin-induced apoptosis in hepatocellular carcinoma cells. Biochem. Biophys. Res. Commun. 427, 581–586.10.1016/j.bbrc.2012.09.101Search in Google Scholar PubMed

Zhu, C., Zhang, L., Zheng, Y., Xu, J., Song, J., Rolfe, B.E., and Campbell, J.H. (2011). Effects of estrogen on stress-induced premature senescence of vascular smooth muscle cells: a novel mechanism for the “time window theory” of menopausal hormone therapy. Atherosclerosis 215, 294–300.10.1016/j.atherosclerosis.2010.12.025Search in Google Scholar PubMed