Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Nhat-Tu LeEmail author
  • Nguyet Minh Hoang
  • Keigi Fujiwara
  • Jun-ichi Abe
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_617



Mitogen-activated protein kinases (MAPKs) are evolutionarily conserved proteins that regulate multiple intracellular processes in all eukaryotic species, from protozoa to plants and vertebrates. Activation of the MAPK family is achieved by three distinct tiers of upstream kinases: The first tier is MAP kinase kinase kinases (MAPKKKs or MAP3Ks), which can respond to various extracellular signals such as mechanical stresses, oxidative stresses, and growth factors, and transduces these extracellular signals into intracellular signaling cascades that regulate various cellular responses. MAPKKKs include MEKK1/2/3/4 and A-/B-/C-Raf (Boulton et al. 1991; Widmann et al. 1999). These kinases activate their downstream...

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  1. Abe J, Berk BC. Novel mechanisms of endothelial mechanotransduction. Arterioscler Thromb Vasc Biol. 2014;34:2378–86.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Abe J, Kusuhara M, Ulevitch RJ, Berk BC, Lee JD. Big mitogen-activated protein kinase 1 (BMK1) is a redox-sensitive kinase. J Biol Chem. 1996;271:16586–90.CrossRefPubMedGoogle Scholar
  3. Akaike M, Che W, Marmarosh NL, Ohta S, Osawa M, Ding B, Berk BC, Yan C, Abe J. The hinge-helix 1 region of peroxisome proliferator-activated receptor gamma1 (PPARgamma1) mediates interaction with extracellular signal-regulated kinase 5 and PPARgamma1 transcriptional activation: involvement in flow-induced PPARgamma activation in endothelial cells. Mol Cell Biol. 2004;24:8691–704.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Akimoto K, Takahashi R, Moriya S, Nishioka N, Takayanagi J, Kimura K, Fukui Y, Osada S, Mizuno K, Hirai S, Kazlauskas A, Ohno S. EGF or PDGF receptors activate atypical PKClambda through phosphatidylinositol 3-kinase. Embo J. 1996;15:788–98.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Akimoto K, Nakaya M, Yamanaka T, Tanaka J, Matsuda S, Weng QP, Avruch J, Ohno S. Atypical protein kinase Clambda binds and regulates p70 S6 kinase. Biochem J. 1998;335(Pt 2):417–24.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Amano S, Chang YT, Fukui Y. ERK5 activation is essential for osteoclast differentiation. PLoS One. 2015;10:e0125054.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Aoki H, Richmond M, Izumo S, Sadoshima J. Specific role of the extracellular signal-regulated kinase pathway in angiotensin II-induced cardiac hypertrophy in vitro. Biochem J. 2000;347(Pt 1):275–84.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Arnoux V, Nassour M, L'Helgoualc'h A, Hipskind RA, Savagner P. Erk5 controls Slug expression and keratinocyte activation during wound healing. Mol Biol Cell. 2008;19:4738–49.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Atkins GB, Jain MK. Role of Kruppel-like transcription factors in endothelial biology. Circ Res. 2007;100:1686–95.CrossRefPubMedGoogle Scholar
  10. Bacabac RG, Smit TH, Mullender MG, Dijcks SJ, Van Loon JJ, Klein-Nulend J. Nitric oxide production by bone cells is fluid shear stress rate dependent. Biochem Biophys Res Commun. 2004;315:823–9.CrossRefPubMedGoogle Scholar
  11. Berra E, Diaz-Meco MT, Dominguez I, Municio MM, Sanz L, Lozano J, Chapkin RS, Moscat J. Protein kinase C zeta isoform is critical for mitogenic signal transduction. Cell. 1993;74:555–63.CrossRefPubMedGoogle Scholar
  12. Bin G, Cuifang W, Bo Z, Jin JJ, Xiaoyi T, Cong C, Yonggang C, Liping A, Jinglin M, Yayi X. Fluid shear stress inhibits TNF-alpha-induced osteoblast apoptosis via ERK5 signaling pathway. Biochem Biophys Res Commun. 2015;466:117–23.CrossRefPubMedGoogle Scholar
  13. Borges J, Pandiella A, Esparis-Ogando A. Erk5 nuclear location is independent on dual phosphorylation, and favours resistance to TRAIL-induced apoptosis. Cell Signal. 2007;19:1473–87.CrossRefPubMedGoogle Scholar
  14. Boulton TG, Nye SH, Robbins DJ, Ip NY, Radziejewska E, Morgenbesser SD, DePinho RA, Panayotatos N, Cobb MH, Yancopoulos GD. ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell. 1991;65:663–75.CrossRefPubMedGoogle Scholar
  15. Bueno OF, De Windt LJ, Tymitz KM, Witt SA, Kimball TR, Klevitsky R, Hewett TE, Jones SP, Lefer DJ, Peng CF, Kitsis RN, Molkentin JD. The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J. 2000;19(23):6341–50.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Buschbeck M, Ullrich A. The unique C-terminal tail of the mitogen-activated protein kinase ERK5 regulates its activation and nuclear shuttling. J Biol Chem. 2005;280:2659–67.CrossRefPubMedGoogle Scholar
  17. Cameron SJ, Abe J, Malik S, Che W, Yang J. Differential role of MEK5alpha and MEK5beta in BMK1/ERK5 activation. J Biol Chem. 2004;279:1506–12.CrossRefPubMedGoogle Scholar
  18. Cavanaugh JE, Ham J, Hetman M, Poser S, Yan C, Xia Z. Differential regulation of mitogen-activated protein kinases ERK1/2 and ERK5 by neurotrophins, neuronal activity, and cAMP in neurons. J Neurosci. 2001;21:434–43.CrossRefPubMedGoogle Scholar
  19. Cecchi E, Giglioli C, Valente S, Lazzeri C, Gensini GF, Abbate R, Mannini L. Role of hemodynamic shear stress in cardiovascular disease. Atherosclerosis. 2011;214:249–56.CrossRefPubMedGoogle Scholar
  20. Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature. 2001;410:37–40.CrossRefPubMedGoogle Scholar
  21. Chao TH, Hayashi M, Tapping RI, Kato Y, Lee JD. MEKK3 directly regulates MEK5 activity as part of the big mitogen-activated protein kinase 1 (BMK1) signaling pathway. J Biol Chem. 1999;274:36035–8.CrossRefPubMedGoogle Scholar
  22. Chayama K, Papst PJ, Garrington TP, Pratt JC, Ishizuka T, Webb S, Ganiatsas S, Zon LI, Sun W, Johnson GL, Gelfand EW. Role of MEKK2-MEK5 in the regulation of TNF-alpha gene expression and MEKK2-MKK7 in the activation of c-Jun N-terminal kinase in mast cells. Proc Natl Acad Sci U S A. 2001;98:4599–604.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Clarke B. Normal bone anatomy and physiology. Clinical J Am Soc Nephrol. 2008;3(Suppl 3):S131–9.CrossRefGoogle Scholar
  24. Colledge M, Scott JD. AKAPs: from structure to function. Trends Cell Biol. 1999;9:216–21.CrossRefPubMedGoogle Scholar
  25. Cude K, Wang Y, Choi HJ, Hsuan SL, Zhang H, Wang CY, Xia Z. Regulation of the G2-M cell cycle progression by the ERK5-NFkappaB signaling pathway. J Cell Biol. 2007;177:253–64.PubMedPubMedCentralCrossRefGoogle Scholar
  26. de Jong PR, et al. ERK5 signalling rescues intestinal epithelial turnover and tumour cell proliferation upon ERK1/2 abrogation. Nat Commun. 2016;7:11551.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Díaz-Rodríguez E, Pandiella A. Multisite phosphorylation of Erk5 in mitosis. J Cell Sci. 2010;123:3146–56. doi:10.1242/jcs.070516.CrossRefPubMedGoogle Scholar
  28. Davis ME, Cai H, McCann L, Fukai T, Harrison DG. Role of c-Src in regulation of endothelial nitric oxide synthase expression during exercise training. Am J Physiol Heart Circ Physiol. 2003;284:H1449–53.CrossRefPubMedGoogle Scholar
  29. Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007;115:1285–95.PubMedGoogle Scholar
  30. Dekker RJ, van Soest S, Fontijn RD, Salamanca S, de Groot PG, VanBavel E, Pannekoek H, Horrevoets AJ. Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Kruppel-like factor (KLF2). Blood. 2002;100:1689–98.CrossRefPubMedGoogle Scholar
  31. Dekker RJ, van Thienen JV, Rohlena J, de Jager SC, Elderkamp YW, Seppen J, de Vries CJ, Biessen EA, van Berkel TJ, Pannekoek H, Horrevoets AJ. Endothelial KLF2 links local arterial shear stress levels to the expression of vascular tone-regulating genes. Am J Pathol. 2005;167:609–18.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP. A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci USA. 2008;105:10762–7.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Diaz-Meco MT, Moscat J. MEK5, a new target of the atypical protein kinase C isoforms in mitogenic signaling. Mol Cell Biol. 2001;21:1218–27.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Diaz-Meco MT, Municio MM, Frutos S, Sanchez P, Lozano J, Sanz L, Moscat J. The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C. Cell. 1996;86:777–86.CrossRefPubMedGoogle Scholar
  35. Diaz-Meco MT, Lallena MJ, Monjas A, Frutos S, Moscat J. Inactivation of the inhibitory kappaB protein kinase/nuclear factor kappaB pathway by Par-4 expression potentiates tumor necrosis factor alpha-induced apoptosis. J Biol Chem. 1999;274:19606–12.CrossRefPubMedGoogle Scholar
  36. Drew BA, Burow ME, Beckman BS. MEK5/ERK5 pathway: the first fifteen years. Biochim Biophys Acta. 2012;1825:37–48.PubMedGoogle Scholar
  37. English JM, Vanderbilt CA, Xu S, Marcus S, Cobb MH. Isolation of MEK5 and differential expression of alternatively spliced forms. J Biol Chem. 1995;270:28897–902.CrossRefPubMedGoogle Scholar
  38. Erazo T, Moreno A, Ruiz-Babot G, Rodriguez-Asiain A, Morrice NA, Espadamala J, Bayascas JR, Gomez N, Lizcano JM. Canonical and kinase activity-independent mechanisms for extracellular signal-regulated kinase 5 (ERK5) nuclear translocation require dissociation of Hsp90 from the ERK5-Cdc37 complex. Mol Cell Biol. 2013;33:1671–86.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Esparis-Ogando A, Diaz-Rodriguez E, Montero JC, Yuste L, Crespo P, Pandiella A. Erk5 participates in neuregulin signal transduction and is constitutively active in breast cancer cells overexpressing ErbB2. Mol Cell Biol. 2002;22:270–85.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Finegan KG, Wang X, Lee EJ, Robinson AC, Tournier C. Regulation of neuronal survival by the extracellular signal-regulated protein kinase 5. Cell Death Differ. 2009;16:674–83.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Forwood MR. Inducible cyclo-oxygenase (COX-2) mediates the induction of bone formation by mechanical loading in vivo. J Bone Miner Res. 1996;11:1688–93.CrossRefPubMedGoogle Scholar
  42. Fritton SP, Weinbaum S. Fluid and Solute Transport in Bone: Flow-Induced Mechanotransduction. Annu Rev Fluid Mech. 2009;41:347–74.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Gao, C., W. Huang, K. Kanasaki, and Y. Xu. 2014. The role of ubiquitination and sumoylation in diabetic nephropathy. BioMed Res Int. 2014;160692.Google Scholar
  44. Geiss-Friedlander R, Melchior F. Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol. 2007;8:947–56.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Gimbrone Jr MA. Endothelial dysfunction, hemodynamic forces, and atherosclerosis. Thromb Haemost. 1999a;82:722–6.CrossRefPubMedGoogle Scholar
  46. Gimbrone Jr MA. Vascular endothelium, hemodynamic forces, and atherogenesis. Am J Pathol. 1999b;155:1–5.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Ginty DD, Segal RA. Retrograde neurotrophin signaling: Trk-ing along the axon. Curr Opin Neurobiol. 2002;12:268–74.CrossRefPubMedGoogle Scholar
  48. Girio A, Montero JC, Pandiella A, Chatterjee S. Erk5 is activated and acts as a survival factor in mitosis. Cell Signal. 2007;19:1964–72.CrossRefPubMedGoogle Scholar
  49. Graos M, Almeida AD, Chatterjee S. Growth-factor-dependent phosphorylation of Bim in mitosis. Biochem J. 2005;388:185–94.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Gray Jr PJ, Stevenson MA, Calderwood SK. Targeting Cdc37 inhibits multiple signaling pathways and induces growth arrest in prostate cancer cells. Cancer Res. 2007;67:11942–50.CrossRefPubMedGoogle Scholar
  51. Gray Jr PJ, Prince T, Cheng J, Stevenson MA, Calderwood SK. Targeting the oncogene and kinome chaperone CDC37. Nat Rev Cancer. 2008;8:491–5.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Green SH, Bailey E, Wang Q, Davis RL. The Trk A, B, C's of neurotrophins in the cochlea. Anat Rec (Hoboken). 2012;295:1877–95.CrossRefGoogle Scholar
  53. Guo B, Yang SH, Witty J, Sharrocks AD. Signalling pathways and the regulation of SUMO modification. Biochem Soc Trans. 2007;35:1414–8.CrossRefPubMedGoogle Scholar
  54. Hamilton JA. CSF-1 signal transduction. J Leukoc Biol. 1997;62:145–55.CrossRefPubMedGoogle Scholar
  55. Hayashi M, Lee JD. Role of the BMK1/ERK5 signaling pathway: lessons from knockout mice. J Mol Med. 2004;82:800–8.CrossRefPubMedGoogle Scholar
  56. Hayashi M, Kim SW, Imanaka-Yoshida K, Yoshida T, Abel ED, Eliceiri B, Yang Y, Ulevitch RJ, Lee JD. Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure. J Clin Invest. 2004;113:1138–48.PubMedPubMedCentralCrossRefGoogle Scholar
  57. Heo KS, Lee H, Nigro P, Thomas T, Le NT, Chang E, McClain C, Reinhart-King CA, King MR, Berk BC, Fujiwara K, Woo CH, Abe J. PKCzeta mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation. J Cell Biol. 2011;193:867–84.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Heo KS, Cushman HJ, Akaike M, Woo CH, Wang X, Qiu X, Fujiwara K, Abe J. ERK5 activation in macrophages promotes efferocytosis and inhibits atherosclerosis. Circulation. 2014;130:180–91.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Heo KS, Le NT, Cushman HJ, Giancursio CJ, Chang E, Woo CH, Sullivan MA, Taunton J, Yeh ET, Fujiwara K, Abe J. Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function. J Clin Invest. 2015;125:1299–310.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Heo KS, Berk BC, Abe JI. Disturbed flow-induced endothelial proatherogenic signaling via regulating post-translational modifications and epigenetic events. Antioxid Redox Signal. 2016;25(7):435–50.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Hilgarth RS, Murphy LA, Skaggs HS, Wilkerson DC, Xing H, Sarge KD. Regulation and function of SUMO modification. J Biol Chem. 2004;279:53899–902.CrossRefPubMedGoogle Scholar
  62. Hillam RA, Skerry TM. Inhibition of bone resorption and stimulation of formation by mechanical loading of the modeling rat ulna in vivo. J Bone Miner Res. 1995;10:683–9.CrossRefPubMedGoogle Scholar
  63. Hillsley MV, Frangos JA. Bone tissue engineering: the role of interstitial fluid flow. Biotechnol Bioeng. 1994;43:573–81.CrossRefPubMedGoogle Scholar
  64. Huddleson JP, Srinivasan S, Ahmad N, Lingrel JB. Fluid shear stress induces endothelial KLF2 gene expression through a defined promoter region. Biol Chem. 2004;385:723–9.CrossRefPubMedGoogle Scholar
  65. Inesta-Vaquera FA, Campbell DG, Tournier C, Gomez N, Lizcano JM, Cuenda A. Alternative ERK5 regulation by phosphorylation during the cell cycle. Cell Signal. 2010;22:1829–37.CrossRefPubMedGoogle Scholar
  66. Jiang J, Zhao LG, Teng YJ, Chen SL, An LP, Ma JL, Wang J, Xia YY. ERK5 signalling pathway is essential for fluid shear stress-induced COX-2 gene expression in MC3T3-E1 osteoblast. Mol Cell Biochem. 2015;406:237–43.CrossRefPubMedGoogle Scholar
  67. Johnson ES. Protein modification by SUMO. Annu Rev Biochem. 2004;73:355–82.PubMedPubMedCentralCrossRefGoogle Scholar
  68. Johnson ES, Blobel G. Ubc9p is the conjugating enzyme for the ubiquitin-like protein Smt3p. J Biol Chem. 1997;272:26799–802.CrossRefPubMedGoogle Scholar
  69. Johnson ES, Schwienhorst I, Dohmen RJ, Blobel G. The ubiquitin-like protein Smt3p is activated for conjugation to other proteins by an Aos1p/Uba2p heterodimer. Embo J. 1997;16:5509–19.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Karnitz LM, Felts SJ. Cdc37 regulation of the kinome: when to hold ’em and when to fold ’em. Sci STKE. 2007;pe22.PubMedCrossRefGoogle Scholar
  71. Kasler HG, Victoria J, Duramad O, Winoto A. ERK5 is a novel type of mitogen-activated protein kinase containing a transcriptional activation domain. Mol Cell Biol. 2000;20:8382–9.PubMedPubMedCentralCrossRefGoogle Scholar
  72. Kato JY, Matsuoka M, Polyak K, Massague J, Sherr CJ. Cyclic AMP-induced G1 phase arrest mediated by an inhibitor (p27Kip1) of cyclin-dependent kinase 4 activation. Cell. 1994;79:487–96.CrossRefPubMedGoogle Scholar
  73. Kato Y, Kravchenko VV, Tapping RI, Han J, Ulevitch RJ, Lee JD. BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C. EMBO J. 1997;16:7054–66.PubMedPubMedCentralCrossRefGoogle Scholar
  74. Kato Y, Tapping RI, Huang S, Watson MH, Ulevitch RJ, Lee JD. Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor. Nature. 1998;395:713–6.CrossRefPubMedGoogle Scholar
  75. Kesavan K, Lobel-Rice K, Sun W, Lapadat R, Webb S, Johnson GL, Garrington TP. MEKK2 regulates the coordinate activation of ERK5 and JNK in response to FGF-2 in fibroblasts. J Cell Physiol. 2004;199:140–8.CrossRefPubMedGoogle Scholar
  76. Kimura TE, Jin J, Zi M, Prehar S, Liu W, Oceandy D, Abe J, Neyses L, Weston AH, Cartwright EJ, Wang X. Targeted deletion of the extracellular signal-regulated protein kinase 5 attenuates hypertrophic response and promotes pressure overload-induced apoptosis in the heart. Circ Res. 2010;106:961–70.PubMedPubMedCentralCrossRefGoogle Scholar
  77. Klein T, Shephard P, Kleinert H, Komhoff M. Regulation of cyclooxygenase-2 expression by cyclic AMP. Biochim Biophys Acta. 2007;1773:1605–18.CrossRefPubMedGoogle Scholar
  78. Kondoh K, Terasawa K, Morimoto H, Nishida E. Regulation of nuclear translocation of extracellular signal-regulated kinase 5 by active nuclear import and export mechanisms. Mol Cell Biol. 2006;26:1679–90.PubMedPubMedCentralCrossRefGoogle Scholar
  79. Korsching S. The neurotrophic factor concept: a reexamination. J Neurosci. 1993;13:2739–48.CrossRefPubMedGoogle Scholar
  80. Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3 T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem. 1991;266:12866–72.PubMedGoogle Scholar
  81. Lamark T, Perander M, Outzen H, Kristiansen K, Overvatn A, Michaelsen E, Bjorkoy G, Johansen T. Interaction codes within the family of mammalian Phox and Bem1p domain-containing proteins. J Biol Chem. 2003;278:34568–81.CrossRefPubMedGoogle Scholar
  82. Lee AW. Atypical protein kinase Cs promote CSF-1-dependent Erk activation and proliferation in myeloid cells. Blood. 2006;108:4227.Google Scholar
  83. Le NT, Corsetti JP, Dehoff-Sparks JL, Sparks CE, Fujiwara K, Abe J. Reactive oxygen species, SUMOylation, and endothelial inflammation. Int J Inflamm. 2012a;678190.Google Scholar
  84. Le NT, Takei Y, Shishido T, Woo CH, Chang E, Heo KS, Lee H, Lu Y, Morrell C, Oikawa M, McClain C, Wang X, Tournier C, Molina CA, Taunton J, Yan C, Fujiwara K, Patterson C, Yang J, Abe J. p90RSK targets the ERK5-CHIP ubiquitin E3 ligase activity in diabetic hearts and promotes cardiac apoptosis and dysfunction. Circ Res. 2012b;110:536–50.PubMedPubMedCentralCrossRefGoogle Scholar
  85. Le NT, Heo KS, Takei Y, Lee H, Woo CH, Chang E, McClain C, Hurley C, Wang X, Li F, Xu H, Morrell C, Sullivan MA, Cohen MS, Serafimova IM, Taunton J, Fujiwara K, Abe J. A crucial role for p90RSK-mediated reduction of ERK5 transcriptional activity in endothelial dysfunction and atherosclerosis. Circulation. 2013;127:486–99.CrossRefPubMedGoogle Scholar
  86. Le NT, Takei Y, Izawa-Ishizawa Y, Heo KS, Lee H, Smrcka AV, Miller BL, Ko KA, Ture S, Morrell C, Fujiwara K, Akaike M, Abe J. Identification of activators of ERK5 transcriptional activity by high-throughput screening and the role of endothelial ERK5 in vasoprotective effects induced by statins and antimalarial agents. J Immunol. 2014;193:3803–15.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Lee JD, Ulevitch RJ, Han J. Primary structure of BMK1: a new mammalian map kinase. Biochem Biophys. 1995;213:715–24.Google Scholar
  88. Lerner-Marmarosh N, Yoshizumi M, Che W, Surapisitchat J, Kawakatsu H, Akaike M, Ding B, Huang Q, Yan C, Berk BC, Abe J. Inhibition of tumor necrosis factor-[alpha]-induced SHP-2 phosphatase activity by shear stress: a mechanism to reduce endothelial inflammation. Arterioscler Thromb Vasc Biol. 2003;23:1775–81.CrossRefPubMedGoogle Scholar
  89. Lewis TS, Shapiro PS, Ahn NG. Signal transduction through MAP kinase cascades. Adv Cancer Res. 1998;74:49–139.CrossRefPubMedGoogle Scholar
  90. Li SJ, Hochstrasser M. A new protease required for cell-cycle progression in yeast. Nature. 1999;398:246–51.CrossRefPubMedGoogle Scholar
  91. Li L, Tatake RJ, Natarajan K, Taba Y, Garin G, Tai C, Leung E, Surapisitchat J, Yoshizumi M, Yan C, Abe J, Berk BC. Fluid shear stress inhibits TNF-mediated JNK activation via MEK5-BMK1 in endothelial cells. Biochem Biophys Res Commun. 2008;370:159–63.PubMedPubMedCentralCrossRefGoogle Scholar
  92. Lin Z, Kumar A, SenBanerjee S, Staniszewski K, Parmar K, Vaughan DE, Gimbrone Jr MA, Balasubramanian V, Garcia-Cardena G, Jain MK. Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function. Circ Res. 2005;96:e48–57.CrossRefPubMedGoogle Scholar
  93. Liu Y, Yin G, Surapisitchat J, Berk BC, Min W. Laminar flow inhibits TNF-induced ASK1 activation by preventing dissociation of ASK1 from its inhibitor 14-3-3. J Clin Invest. 2001;107:917–23.PubMedPubMedCentralCrossRefGoogle Scholar
  94. Liu L, Cavanaugh JE, Wang Y, Sakagami H, Mao Z, Xia Z. ERK5 activation of MEF2-mediated gene expression plays a critical role in BDNF-promoted survival of developing but not mature cortical neurons. Proc Natl Acad Sci U S A. 2003;100:8532–7.PubMedPubMedCentralCrossRefGoogle Scholar
  95. MacLellan WR, Schneider MD. Genetic dissection of cardiac growth control pathways. Annu Rev Physiol. 2000;62:289–319.PubMedPubMedCentralCrossRefGoogle Scholar
  96. McAllister TN, Du T, Frangos JA. Fluid shear stress stimulates prostaglandin and nitric oxide release in bone marrow-derived preosteoclast-like cells. Biochem Biophys Res Commun. 2000;270:643–8.CrossRefPubMedGoogle Scholar
  97. McClellan AJ, Xia Y, Deutschbauer AM, Davis RW, Gerstein M, Frydman J. Diverse cellular functions of the Hsp90 molecular chaperone uncovered using systems approaches. Cell. 2007;131:121–35.CrossRefPubMedGoogle Scholar
  98. Mehta PB, Jenkins BL, McCarthy L, Thilak L, Robson CN, Neal DE, Leung HY. MEK5 overexpression is associated with metastatic prostate cancer, and stimulates proliferation, MMP-9 expression and invasion. Oncogene. 2003;22:1381–9.CrossRefPubMedGoogle Scholar
  99. Mochly-Rosen D. Localization of protein kinases by anchoring proteins: a theme in signal transduction. Science. 1995;268:247–51.CrossRefPubMedGoogle Scholar
  100. Mochly-Rosen D, Gordon AS. Anchoring proteins for protein kinase C: a means for isozyme selectivity. FASEB J. 1998;12:35–42.CrossRefPubMedGoogle Scholar
  101. Mody N, Campbell DG, Morrice N, Peggie M, Cohen P. An analysis of the phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (ERK5) by mitogen-activated protein kinase kinase 5 (MKK5) in vitro. Biochem J. 2003;372:567–75.PubMedPubMedCentralCrossRefGoogle Scholar
  102. Morimoto H, Kondoh K, Nishimoto S, Terasawa K, Nishida E. Activation of a C-terminal transcriptional activation domain of ERK5 by autophosphorylation. J Biol Chem. 2007;282:35449–56.CrossRefPubMedGoogle Scholar
  103. Moscat J, Diaz-Meco MT. The atypical protein kinase Cs. Functional specificity mediated by specific protein adapters. 2000. Review.PubMedPubMedCentralCrossRefGoogle Scholar
  104. Nagel T, Resnick N, Dewey Jr CF, Gimbrone Jr MA. Vascular endothelial cells respond to spatial gradients in fluid shear stress by enhanced activation of transcription factors. Arterioscler Thromb Vasc Biol. 1999;19:1825–34.CrossRefPubMedGoogle Scholar
  105. Nakamura K, Johnson GL. PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway. J Biol Chem. 2003;278:36989–92.CrossRefPubMedGoogle Scholar
  106. Nakamura K, Johnson GL. Noncanonical function of MEKK2 and MEK5 PB1 domains for coordinated extracellular signal-regulated kinase 5 and c-Jun N-terminal kinase signaling. Mol Cell Biol. 2007;27:4566–77.PubMedPubMedCentralCrossRefGoogle Scholar
  107. Nakamura K, Uhlik MT, Johnson NL, Hahn KM, Johnson GL. PB1 domain-dependent signaling complex is required for extracellular signal-regulated kinase 5 activation. Mol Cell Biol. 2006;26:2065–79.PubMedPubMedCentralCrossRefGoogle Scholar
  108. Nicol RL, Frey N, Pearson G, Cobb M, Richardson J, Olson EN. Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy. EMBO J. 2001;20:2757–67.PubMedPubMedCentralCrossRefGoogle Scholar
  109. Nigro P, Abe J, Woo CH, Satoh K, McClain C, O'Dell MR, Lee H, Lim JH, Li JD, Heo KS, Fujiwara K, Berk BC. PKCzeta decreases eNOS protein stability via inhibitory phosphorylation of ERK5. Blood. 2010a;116:1971–9.PubMedPubMedCentralCrossRefGoogle Scholar
  110. Nigro P, Abe JI, Woo CH, Satoh K, McClain C, O’Dell MR, Lee H, Lim JH, Li JD, Heo KS, Fujiwara K, Berk BC. PKC{zeta} decreases eNOS protein stability via inhibitory phosphorylation of ERK5. Blood. 2010b;116(11):1971–9.PubMedPubMedCentralCrossRefGoogle Scholar
  111. Nishida E, Gotoh Y. The MAP kinase cascade is essential for diverse signal transduction pathways. Trends Biochem Sci. 1993;18:128–31.CrossRefPubMedGoogle Scholar
  112. Nishimoto S, Nishida E. MAPK signalling: ERK5 versus ERK1/2. EMBO Rep. 2006;7:782–6.PubMedPubMedCentralCrossRefGoogle Scholar
  113. Nuez B, Michalovich D, Bygrave A, Ploemacher R, Grosveld F. Defective haematopoiesis in fetal liver resulting from inactivation of the EKLF gene. Nature. 1995;375:316–8.CrossRefPubMedGoogle Scholar
  114. Ogasawara A, Arakawa T, Kaneda T, Takuma T, Sato T, Kaneko H, Kumegawa M, Hakeda Y. Fluid shear stress-induced cyclooxygenase-2 expression is mediated by C/EBP beta, cAMP-response element-binding protein, and AP-1 in osteoblastic MC3T3-E1 cells. J Biol Chem. 2001;276:7048–54.CrossRefPubMedGoogle Scholar
  115. Osaki LH, Gama P. MAPKs and signal transduction in the control of gastrointestinal epithelial cell proliferation and differentiation. Int J Mol Sci. 2013;14:10143–61.PubMedPubMedCentralCrossRefGoogle Scholar
  116. Parmar KM, Larman HB, Dai G, Zhang Y, Wang ET, Moorthy SN, Kratz JR, Lin Z, Jain MK, Gimbrone Jr MA, Garcia-Cardena G. Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. J Clin Invest. 2006;116:49–58.CrossRefPubMedGoogle Scholar
  117. Pearl LH, Prodromou C. Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu Rev Biochem. 2006;75:271–94.PubMedCrossRefGoogle Scholar
  118. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22:153–83.PubMedGoogle Scholar
  119. Piper PW. The Hsp90 chaperone as a promising drug target. Curr Opin Investig Drugs. 2001;2:1606–10.PubMedGoogle Scholar
  120. Piper PW, Millson SH, Mollapour M, Panaretou B, Siligardi G, Pearl LH, Prodromou C. Sensitivity to Hsp90-targeting drugs can arise with mutation to the Hsp90 chaperone, cochaperones and plasma membrane ATP binding cassette transporters of yeast. Eur J Biochem. 2003;270:4689–95.CrossRefPubMedGoogle Scholar
  121. Plotnikov A, Zehorai E, Procaccia S, Seger R. The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim Biophys Acta. 2011;1813:1619–33.CrossRefPubMedGoogle Scholar
  122. Ponting CP, Ito T, Moscat J, Diaz-Meco MT, Inagaki F, Sumimoto H. OPR, PC and AID: all in the PB1 family. Trends Biochem Sci. 2002;27:10.CrossRefPubMedGoogle Scholar
  123. Prodromou C, Roe SM, O'Brien R, Ladbury JE, Piper PW, Pearl LH. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell. 1997;90:65–75.CrossRefPubMedGoogle Scholar
  124. Qi M, Elion EA. MAP kinase pathways. J Cell Sci. 2005;118:3569–72.CrossRefPubMedGoogle Scholar
  125. Raviv Z, Kalie E, Seger R. MEK5 and ERK5 are localized in the nuclei of resting as well as stimulated cells, while MEKK2 translocates from the cytosol to the nucleus upon stimulation. J Cell Sci. 2004;117:1773–84.CrossRefPubMedGoogle Scholar
  126. Regan CP, Li W, Boucher DM, Spatz S, Su MS, Kuida K. Erk5 null mice display multiple extraembryonic vascular and embryonic cardiovascular defects. Proc Natl Acad Sci USA. 2002;99:9248–53.PubMedPubMedCentralCrossRefGoogle Scholar
  127. Roberts OL, Holmes K, Muller J, Cross DA, Cross MJ. ERK5 and the regulation of endothelial cell function. Biochem Soc Trans. 2009;37:1254–9.CrossRefPubMedGoogle Scholar
  128. Robinson MJ, Cobb MH. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol. 1997;9:180–6.CrossRefPubMedGoogle Scholar
  129. Roe SM, Ali MM, Meyer P, Vaughan CK, Panaretou B, Piper PW, Prodromou C, Pearl LH. The Mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50(cdc37). Cell. 2004;116:87–98.CrossRefPubMedGoogle Scholar
  130. Rovida E, Navari N, Caligiuri A, Dello Sbarba P, Marra F. ERK5 differentially regulates PDGF-induced proliferation and migration of hepatic stellate cells. J Hepatol. 2008a;48:107–15.CrossRefPubMedGoogle Scholar
  131. Rovida E, Spinelli E, Sdelci S, Barbetti V, Morandi A, Giuntoli S, Dello Sbarba P. ERK5/BMK1 is indispensable for optimal colony-stimulating factor 1 (CSF-1)-induced proliferation in macrophages in a Src-dependent fashion. J Immunol. 2008b;180:4166–72.CrossRefPubMedGoogle Scholar
  132. Sanchez P, De Carcer G, Sandoval IV, Moscat J, Diaz-Meco MT. Localization of atypical protein kinase C isoforms into lysosome-targeted endosomes through interaction with p62. Mol Cell Biol. 1998;18:3069–80.PubMedPubMedCentralCrossRefGoogle Scholar
  133. Sanz L, Sanchez P, Lallena MJ, Diaz-Meco MT, Moscat J. The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation. Embo J. 1999;18:3044–53.PubMedPubMedCentralCrossRefGoogle Scholar
  134. Savagner P, Kusewitt DF, Carver EA, Magnino F, Choi C, Gridley T, Hudson LG. Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes. J Cell Physiol. 2005;202:858–66.CrossRefPubMedGoogle Scholar
  135. Schulte TW, Akinaga S, Soga S, Sullivan W, Stensgard B, Toft D, Neckers LM. Antibiotic radicicol binds to the N-terminal domain of Hsp90 and shares important biologic activities with geldanamycin. Cell Stress Chaperones. 1998;3:100–8.PubMedPubMedCentralCrossRefGoogle Scholar
  136. Schulte TW, Akinaga S, Murakata T, Agatsuma T, Sugimoto S, Nakano H, Lee YS, Simen BB, Argon Y, Felts S, Toft DO, Neckers LM, Sharma SV. Interaction of radicicol with members of the heat shock protein 90 family of molecular chaperones. Mol Endocrinol. 1999;13:1435–48.CrossRefPubMedGoogle Scholar
  137. Seger R, Krebs EG. The MAPK signaling cascade. Faseb J. 1995;9:726–35.CrossRefPubMedGoogle Scholar
  138. SenBanerjee S, Lin Z, Atkins GB, Greif DM, Rao RM, Kumar A, Feinberg MW, Chen Z, Simon DI, Luscinskas FW, Michel TM, Gimbrone Jr MA, Garcia-Cardena G, Jain MK. KLF2 is a novel transcriptional regulator of endothelial proinflammatory activation. J Exp Med. 2004;199:1305–15.PubMedPubMedCentralCrossRefGoogle Scholar
  139. Seyfried J, Wang X, Kharebava G, Tournier C. A novel mitogen-activated protein kinase docking site in the N terminus of MEK5alpha organizes the components of the extracellular signal-regulated kinase 5 signaling pathway. Mol Cell Biol. 2005;25:9820–8.PubMedPubMedCentralCrossRefGoogle Scholar
  140. Song H, Jin X, Lin J. Stat3 upregulates MEK5 expression in human breast cancer cells. Oncogene. 2004;23:8301–9.CrossRefPubMedGoogle Scholar
  141. Spiering D, Schmolke M, Ohnesorge N, Schmidt M, Goebeler M, Wegener J, Wixler V, Ludwig S. MEK5/ERK5 signaling modulates endothelial cell migration and focal contact turnover. J Biol Chem. 2009;284:24972–80.PubMedPubMedCentralCrossRefGoogle Scholar
  142. Stanley ER, Berg KL, Einstein DB, Lee PS, Pixley FJ, Wang Y, Yeung YG. Biology and action of colony-stimulating factor-1. Mol Reprod Dev. 1997;46:4–10.CrossRefPubMedGoogle Scholar
  143. Steinberg SF. Structural basis of protein kinase C isoform function. Physiol Rev. 2008;88:1341–78.PubMedPubMedCentralCrossRefGoogle Scholar
  144. Su C, Underwood W, Rybalchenko N, Singh M. ERK1/2 and ERK5 have distinct roles in the regulation of brain-derived neurotrophic factor expression. J Neurosci Res. 2011;89:1542–50.CrossRefPubMedGoogle Scholar
  145. Sumimoto H, Kamakura S, Ito T. Structure and function of the PB1 domain, a protein interaction module conserved in animals, fungi, amoebas, and plants. Sci STKE. 2007;re6.PubMedCrossRefGoogle Scholar
  146. Sun W, Kesavan K, Schaefer BC, Garrington TP, Ware M, Johnson NL, Gelfand EW, Johnson GL. MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway. J Biol Chem. 2001;276:5093–100.CrossRefPubMedGoogle Scholar
  147. Sun W, Wei X, Kesavan K, Garrington TP, Fan R, Mei J, Anderson SM, Gelfand EW, Johnson GL. MEK kinase 2 and the adaptor protein Lad regulate extracellular signal-regulated kinase 5 activation by epidermal growth factor via Src. Mol Cell Biol. 2003;23:2298–308.PubMedPubMedCentralCrossRefGoogle Scholar
  148. Surapisitchat J, Hoefen RJ, Pi X, Yoshizumi M, Yan C, Berk BC. Fluid shear stress inhibits TNF-alpha activation of JNK but not ERK1/2 or p38 in human umbilical vein endothelial cells: Inhibitory crosstalk among MAPK family members. Proc Natl Acad Sci USA. 2001;98:6476–81.PubMedPubMedCentralCrossRefGoogle Scholar
  149. Terasawa K, Okazaki K, Nishida E. Regulation of c-Fos and Fra-1 by the MEK5-ERK5 pathway. Genes Cells. 2003;8:263–73.CrossRefPubMedGoogle Scholar
  150. Tomita H, Nazmy M, Kajimoto K, Yehia G, Molina CA, Sadoshima J. Inducible cAMP early repressor (ICER) is a negative-feedback regulator of cardiac hypertrophy and an important mediator of cardiac myocyte apoptosis in response to beta-adrenergic receptor stimulation. Circ Res. 2003;93:12–22.CrossRefPubMedGoogle Scholar
  151. Topper JN, Gimbrone Jr MA. Blood flow and vascular gene expression: fluid shear stress as a modulator of endothelial phenotype. Mol Med Today. 1999;5:40–6.CrossRefPubMedGoogle Scholar
  152. Topper JN, Cai J, Qiu Y, Anderson KR, Xu YY, Deeds JD, Feeley R, Gimeno CJ, Woolf EA, Tayber O, Mays GG, Sampson BA, Schoen FJ, Gimbrone Jr MA, Falb D. Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium. Proc Natl Acad Sci U S A. 1997;94:9314–9.PubMedPubMedCentralCrossRefGoogle Scholar
  153. Tousoulis D, Charakida M, Stefanadis C. Endothelial function and inflammation in coronary artery disease. Heart. 2006;92:441–4.PubMedGoogle Scholar
  154. Traub O, Berk BC. Laminar shear stress: mechanisms by which endothelial cells transduce an atheroprotective force. Arterioscler Thromb Vasc Biol. 1998;18:677–85.CrossRefPubMedGoogle Scholar
  155. Urbich C, Stein M, Reisinger K, Kaufmann R, Dimmeler S, Gille J. Fluid shear stress-induced transcriptional activation of the vascular endothelial growth factor receptor-2 gene requires Sp1-dependent DNA binding. FEBS Lett. 2003;535:87–93.CrossRefPubMedGoogle Scholar
  156. Verger A, Perdomo J, Crossley M. Modification with SUMO: a role in transcriptional regulation. EMBO Rep. 2003;4:137–42.PubMedPubMedCentralCrossRefGoogle Scholar
  157. Wang X, Tournier C. Regulation of cellular functions by the ERK5 signalling pathway. Cell Signal. 2006;18:753–60.CrossRefPubMedGoogle Scholar
  158. Wang YM, Seibenhener ML, Vandenplas ML, Wooten MW. Atypical PKC zeta is activated by ceramide, resulting in coactivation of NF-kappaB/JNK kinase and cell survival. J Neurosci Res. 1999;55:293–302.CrossRefPubMedGoogle Scholar
  159. Wang N, Miao H, Li YS, Zhang P, Haga JH, Hu Y, Young A, Yuan S, Nguyen P, Wu CC, Chien S. Shear stress regulation of Kruppel-like factor 2 expression is flow pattern-specific. Biochem Biophys Res Commun. 2006a;341:1244–51.CrossRefPubMedGoogle Scholar
  160. Wang Y, Su B, Xia Z. Brain-derived neurotrophic factor activates ERK5 in cortical neurons via a Rap1-MEKK2 signaling cascade. J Biol Chem. 2006b;281:35965–74.CrossRefPubMedGoogle Scholar
  161. Wang X, Tournier C. Regulation of cellular functions by the ERK5 signalling pathway. Cell Signal. 2006;18:753–60.CrossRefPubMedGoogle Scholar
  162. Watson FL, Heerssen HM, Bhattacharyya A, Klesse L, Lin MZ, Segal RA. Neurotrophins use the Erk5 pathway to mediate a retrograde survival response. Nat Neurosci. 2001;4:981–8.CrossRefPubMedGoogle Scholar
  163. Weldon CB, Scandurro AB, Rolfe KW, Clayton JL, Elliott S, Butler NN, Melnik LI, Alam J, McLachlan JA, Jaffe BM, Beckman BS, Burow ME. Identification of mitogen-activated protein kinase kinase as a chemoresistant pathway in MCF-7 cells by using gene expression microarray. Surgery. 2002;132:293–301.CrossRefPubMedGoogle Scholar
  164. Widmann C, Gibson S, Jarpe MB, Johnson GL. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev. 1999;79:143–80.CrossRefPubMedGoogle Scholar
  165. Wilkinson KA, Henley JM. Mechanisms, regulation and consequences of protein SUMOylation. Biochem J. 2010;428:133–45.PubMedPubMedCentralCrossRefGoogle Scholar
  166. Wilson MI, Gill DJ, Perisic O, Quinn MT, Williams RL. PB1 domain-mediated heterodimerization in NADPH oxidase and signaling complexes of atypical protein kinase C with Par6 and p62. Mol Cell. 2003;12:39–50.CrossRefPubMedGoogle Scholar
  167. Woo CH, Abe J. SUMO--a post-translational modification with therapeutic potential? Curr Opin Pharmacol. 2010;10:146–55.PubMedPubMedCentralCrossRefGoogle Scholar
  168. Woo CH, Shishido T, McClain C, Lim JH, Li JD, Yang J, Yan C, Abe J. Extracellular signal-regulated kinase 5 SUMOylation antagonizes shear stress-induced antiinflammatory response and endothelial nitric oxide synthase expression in endothelial cells. Circ Res. 2008;102:538–45.CrossRefPubMedGoogle Scholar
  169. Woo CH, Le NT, Shishido T, Chang E, Lee H, Heo KS, Mickelsen DM, Lu Y, McClain C, Spangenberg T, Yan C, Molina CA, Yang J, Patterson C, Abe J. Novel role of C terminus of Hsc70-interacting protein (CHIP) ubiquitin ligase on inhibiting cardiac apoptosis and dysfunction via regulating ERK5-mediated degradation of inducible cAMP early repressor. FASEB J. 2010;24:4917–28.PubMedPubMedCentralCrossRefGoogle Scholar
  170. Yamawaki H, Lehoux S, Berk BC. Chronic physiological shear stress inhibits tumor necrosis factor-induced proinflammatory responses in rabbit aorta perfused ex vivo. Circulation. 2003;108:1619–25.CrossRefPubMedGoogle Scholar
  171. Yamawaki H, Pan S, Lee RT, Berk BC. Fluid shear stress inhibits vascular inflammation by decreasing thioredoxin-interacting protein in endothelial cells. J Clin Invest. 2005;115:733–8.PubMedPubMedCentralCrossRefGoogle Scholar
  172. Yan C, Luo H, Lee JD, Abe J, Berk BC. Molecular cloning of mouse ERK5/BMK1 splice variants and characterization of ERK5 functional domains. J Biol Chem. 2001;276:10870–8.CrossRefPubMedGoogle Scholar
  173. Yan L, Carr J, Ashby PR, Murry-Tait V, Thompson C, Arthur JS. Knockout of ERK5 causes multiple defects in placental and embryonic development. BMC Dev Biol. 2003;3:11.PubMedPubMedCentralCrossRefGoogle Scholar
  174. Yang SH, Sharrocks AD, Whitmarsh AJ. Transcriptional regulation by the MAP kinase signaling cascades. Gene. 2003;320:3–21.CrossRefPubMedGoogle Scholar
  175. Yeh ET. SUMOylation and De-SUMOylation: wrestling with life’s processes. J Biol Chem. 2009;284:8223–7.PubMedPubMedCentralCrossRefGoogle Scholar
  176. Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors. 2006;24:21–44.CrossRefPubMedGoogle Scholar
  177. Yu SJ, Grider JR, Gulick MA, Xia CM, Shen S, Qiao LY. Up-regulation of brain-derived neurotrophic factor is regulated by extracellular signal-regulated protein kinase 5 and by nerve growth factor retrograde signaling in colonic afferent neurons in colitis. Exp Neurol. 2012;238:209–17.PubMedPubMedCentralCrossRefGoogle Scholar
  178. Zhang Y, Dong C. Regulatory mechanisms of mitogen-activated kinase signaling. Cell Mol Life Sci. 2007;64:2771–89.CrossRefPubMedGoogle Scholar
  179. Zhang W, Elimban V, Nijjar MS, Gupta SK, Dhalla NS. Role of mitogen-activated protein kinase in cardiac hypertrophy and heart failure. Exp Clin Cardiol. 2003;8:173–83.PubMedPubMedCentralGoogle Scholar
  180. Zhang C, Xu Z, He XR, Michael LH, Patterson C. CHIP, a cochaperone/ubiquitin ligase that regulates protein quality control, is required for maximal cardioprotection after myocardial infarction in mice. Am J Physiol Heart Circ Physiol. 2005;288:H2836–42.CrossRefPubMedGoogle Scholar
  181. Zhao LG, Chen SL, Teng YJ, An LP, Wang J, Ma JL, Xia YY. The MEK5/ERK5 pathway mediates fluid shear stress promoted osteoblast differentiation. Connect Tissue Res. 2014;55:96–102.CrossRefPubMedGoogle Scholar
  182. Zhou G, Bao ZQ, Dixon JE. Components of a new human protein kinase signal transduction pathway. J Biol Chem. 1995;270:12665–9.CrossRefPubMedGoogle Scholar
  183. Zhou C, Nitschke AM, Xiong W, Zhang Q, Tang Y, Bloch M, Elliott S, Zhu Y, Bazzone L, Yu D, Weldon CB, Schiff R, McLachlan JA, Beckman BS, Wiese TE, Nephew KP, Shan B, Burow ME, Wang G. Proteomic analysis of tumor necrosis factor-alpha resistant human breast cancer cells reveals a MEK5/Erk5-mediated epithelial-mesenchymal transition phenotype. Breast Cancer Res. 2008;10:R105.PubMedPubMedCentralCrossRefGoogle Scholar
  184. Zou J, Pan YW, Wang Z, Chang SY, Wang W, Wang X, Tournier C, Storm DR, Xia Z. Targeted deletion of ERK5 MAP kinase in the developing nervous system impairs development of GABAergic interneurons in the main olfactory bulb and behavioral discrimination between structurally similar odorants. J Neurosci. 2012;32:4118–32.PubMedPubMedCentralCrossRefGoogle Scholar
  185. Zou J, Storm DR, Xia Z. Conditional deletion of ERK5 MAP kinase in the nervous system impairs pheromone information processing and pheromone-evoked behaviors. PLoS One. 2013;8:e76901.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Nhat-Tu Le
    • 1
    Email author
  • Nguyet Minh Hoang
    • 1
  • Keigi Fujiwara
    • 1
  • Jun-ichi Abe
    • 1
  1. 1.Department of CardiologyThe University of Texas, MD Anderson Cancer CenterHoustonUSA