mitogen activated protein kinase 7


Summary: A 110-kDa extracellular signal-regulated MAP kinase that is activated in response to cellular stress and by GROWTH FACTOR RECEPTORS-mediated pathways.

Top Publications

  1. Nicol R, Frey N, Pearson G, Cobb M, Richardson J, Olson E. Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy. EMBO J. 2001;20:2757-67 pubmed
    ..These findings reveal a specific role for MEK5-ERK5 in the induction of eccentric cardiac hypertrophy and in transduction of cytokine signals that regulate serial sarcomere assembly. ..
  2. Garaude J, Cherni S, Kaminski S, Delepine E, Chable Bessia C, Benkirane M, et al. ERK5 activates NF-kappaB in leukemic T cells and is essential for their growth in vivo. J Immunol. 2006;177:7607-17 pubmed
    ..c. tumors in mice. Our results suggest that ERK5 is essential for survival of leukemic T cells in vivo, and thus represents a promising target for therapeutic intervention in this type of malignancy. ..
  3. Sohn S, Sarvis B, Cado D, Winoto A. ERK5 MAPK regulates embryonic angiogenesis and acts as a hypoxia-sensitive repressor of vascular endothelial growth factor expression. J Biol Chem. 2002;277:43344-51 pubmed
    ..Importantly, ERK5 is required at an earlier developmental stage than p38alpha, and p38alpha does not compensate for ERK5 deficiency. These results demonstrate that ERK5 plays a specific role in the regulation of early angiogenesis. ..
  4. Liu L, Cavanaugh J, 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 pubmed
    ..These data suggest that ERK5 activation of myocyte enhancer factor 2-induced gene expression may play an important and novel role in the development of the CNS by mediating NT-promoted survival of embryonic neurons. ..
  5. Shalizi A, Lehtinen M, Gaudilliere B, Donovan N, Han J, Konishi Y, et al. Characterization of a neurotrophin signaling mechanism that mediates neuron survival in a temporally specific pattern. J Neurosci. 2003;23:7326-36 pubmed
    ..These findings define a novel mechanism that underlies the antiapoptotic effect of neurotrophins in a temporally defined pattern in the developing mammalian brain. ..
  6. Cavanaugh J, 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 pubmed
    ..Furthermore, ERK5 is the first MAP kinase identified whose activity is stimulated by neurotrophins but not by neuronal activity. ..
  7. Pearson G, English J, White M, Cobb M. ERK5 and ERK2 cooperate to regulate NF-kappaB and cell transformation. J Biol Chem. 2001;276:7927-31 pubmed
    ..Our results support the hypothesis that NF-kappaB and p90 ribosomal S6 kinase are involved in MEK5-ERK5-dependent focus formation and may serve as integration points for ERK5 and ERK1/2 signaling. ..
  8. Hayashi M, Kim S, Imanaka Yoshida K, Yoshida T, Abel E, Eliceiri B, et al. Targeted deletion of BMK1/ERK5 in adult mice perturbs vascular integrity and leads to endothelial failure. J Clin Invest. 2004;113:1138-48 pubmed
    ..Taken together, the data provide direct genetic evidence that the BMK1 pathway is critical for endothelial function and for maintaining blood vessel integrity. ..
  9. Chao T, Hayashi M, Tapping R, Kato Y, Lee J. 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 pubmed
    ..Taken together, these results identify MEKK3 as a kinase that regulates the activity of MEK5 and BMK1 during growth factor-induced cellular stimulation. ..

More Information


  1. Cavanaugh J. Role of extracellular signal regulated kinase 5 in neuronal survival. Eur J Biochem. 2004;271:2056-9 pubmed
    ..These data also suggest that the mechanism of ERK5-mediated survival involves transcriptional regulation. ..
  2. Buschbeck M, Hofbauer S, Di Croce L, Keri G, Ullrich A. Abl-kinase-sensitive levels of ERK5 and its intrinsic basal activity contribute to leukaemia cell survival. EMBO Rep. 2005;6:63-9 pubmed
    ..These results suggest that the ability to regulate the cellular abundance of ERK5 contributes to the oncogenic potential of Abl kinases. ..
  3. 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 pubmed
    ..Altogether these results establish that the N terminus of MEK5alpha is critical for the specific organization of the components of the ERK5 signaling pathway. ..
  4. Barsyte Lovejoy D, Galanis A, Clancy A, Sharrocks A. ERK5 is targeted to myocyte enhancer factor 2A (MEF2A) through a MAPK docking motif. Biochem J. 2004;381:693-9 pubmed
    ..Our data therefore extend previous observations on other MAPKs and demonstrate that the requirement for specific docking domains in promoting MAPK action towards substrates is a general property of MAPKs. ..
  5. Barros J, Marshall C. Activation of either ERK1/2 or ERK5 MAP kinase pathways can lead to disruption of the actin cytoskeleton. J Cell Sci. 2005;118:1663-71 pubmed
    ..Our results suggest that multiple MAP kinase pathways downstream of oncogenes participate in cytoskeletal alterations. ..
  6. Pi X, Yan C, Berk B. Big mitogen-activated protein kinase (BMK1)/ERK5 protects endothelial cells from apoptosis. Circ Res. 2004;94:362-9 pubmed
    ..These results suggest that BMK1 activation by steady laminar flow is atheroprotective by inhibiting EC apoptosis via phosphorylation of Bad. ..
  7. Ranganathan A, Pearson G, Chrestensen C, Sturgill T, Cobb M. The MAP kinase ERK5 binds to and phosphorylates p90 RSK. Arch Biochem Biophys. 2006;449:8-16 pubmed
    ..The large C-terminal domain of ERK5 is not required for binding or activation of RSK by ERK5; however, the common docking or CD domain of ERK5 and the docking or D domain of RSK are important for their association. ..
  8. Liu L, Cundiff P, Abel G, Wang Y, Faigle R, Sakagami H, et al. Extracellular signal-regulated kinase (ERK) 5 is necessary and sufficient to specify cortical neuronal fate. Proc Natl Acad Sci U S A. 2006;103:9697-702 pubmed
  9. Terasawa K, Okazaki K, Nishida E. Regulation of c-Fos and Fra-1 by the MEK5-ERK5 pathway. Genes Cells. 2003;8:263-73 pubmed
    ..These results reveal a role of the MEK5-ERK5 pathway in modulating the function of the Fos family proteins which is different from the role of the ERK1/2 pathway. ..
  10. Schramp M, Ying O, Kim T, Martin G. ERK5 promotes Src-induced podosome formation by limiting Rho activation. J Cell Biol. 2008;181:1195-210 pubmed publisher
    ..We conclude that ERK5 promotes Src-induced podosome formation by inducing RhoGAP7 and thereby limiting Rho activation. ..
  11. Watson F, Heerssen H, Bhattacharyya A, Klesse L, Lin M, Segal R. Neurotrophins use the Erk5 pathway to mediate a retrograde survival response. Nat Neurosci. 2001;4:981-8 pubmed
    ..Differential activation of distinct MAPK pathways may enable an individual growth factor to relay information that specifies the location and the nature of stimulation. ..
  12. Mody N, Leitch J, Armstrong C, Dixon J, Cohen P. Effects of MAP kinase cascade inhibitors on the MKK5/ERK5 pathway. FEBS Lett. 2001;502:21-4 pubmed
    ..Our results also indicate that ERK5 is not a significant activator of MAPK-activated protein kinase-1/RSK in HeLa cells. ..
  13. Kato Y, Tapping R, Huang S, Watson M, Ulevitch R, Lee J. Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor. Nature. 1998;395:713-6 pubmed
    ..These results demonstrate that Bmk1 is part of a distinct MAP-kinase signalling pathway that is required for EGF-induced cell proliferation and progression through the cell cycle. ..
  14. Hayashi M, Lee J. Role of the BMK1/ERK5 signaling pathway: lessons from knockout mice. J Mol Med (Berl). 2004;82:800-8 pubmed
  15. Cude K, Wang Y, Choi H, Hsuan S, Zhang H, Wang C, et al. Regulation of the G2-M cell cycle progression by the ERK5-NFkappaB signaling pathway. J Cell Biol. 2007;177:253-64 pubmed
    ..We conclude that a novel ERK5-NFkappaB signaling pathway plays a key role in regulation of the G2-M progression. ..
  16. Nishimoto S, Nishida E. MAPK signalling: ERK5 versus ERK1/2. EMBO Rep. 2006;7:782-6 pubmed
  17. Wang X, Finegan K, Robinson A, Knowles L, Khosravi Far R, Hinchliffe K, et al. Activation of extracellular signal-regulated protein kinase 5 downregulates FasL upon osmotic stress. Cell Death Differ. 2006;13:2099-108 pubmed
    ..Based on these results, we conclude that the ERK5 signaling pathway promotes cell survival by downregulating FasL expression via a mechanism that implicates PKB-dependent inhibition of Foxo3a downstream of phosphoinositide 3 kinase. ..
  18. Kato Y, Kravchenko V, Tapping R, Han J, Ulevitch R, Lee J. BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C. EMBO J. 1997;16:7054-66 pubmed
    ..Taken together, these results strongly suggest that in some cell types the MEK5/BMK1 MAP kinase signaling pathway regulates serum-induced early gene expression through the transcription factor MEF2C. ..
  19. Wang X, Tournier C. Regulation of cellular functions by the ERK5 signalling pathway. Cell Signal. 2006;18:753-60 pubmed
    ..The analysis of genetically modified mice in which the erk5 gene can be specifically deleted in certain tissues is shedding light into the physiological function of the ERK5 pathway during development and pathogenesis. ..
  20. English J, Pearson G, Baer R, Cobb M. Identification of substrates and regulators of the mitogen-activated protein kinase ERK5 using chimeric protein kinases. J Biol Chem. 1998;273:3854-60 pubmed
    ..Thus, ERK5 is a target of a novel Ras effector pathway that may communicate with c-Myc. ..
  21. Nishimoto S, Kusakabe M, Nishida E. Requirement of the MEK5-ERK5 pathway for neural differentiation in Xenopus embryonic development. EMBO Rep. 2005;6:1064-9 pubmed
    ..These results show that the MEK5-ERK5 pathway has an essential role in the regulation of neural differentiation downstream of SoxD and upstream of Xngnr1. ..
  22. Yang C, Ornatsky O, McDermott J, Cruz T, Prody C. Interaction of myocyte enhancer factor 2 (MEF2) with a mitogen-activated protein kinase, ERK5/BMK1. Nucleic Acids Res. 1998;26:4771-7 pubmed
    ..Furthermore, when cotransfected with ERK5/BMK1, the transactivation capacity of MEF2 was enhanced. These results suggest that the functions of MEF2 could be regulated through ERK5/BMK1. ..
  23. Reddy S, Adiseshaiah P, Shapiro P, Vuong H. BMK1 (ERK5) regulates squamous differentiation marker SPRR1B transcription in Clara-like H441 cells. Am J Respir Cell Mol Biol. 2002;27:64-70 pubmed
    ..Thus, in addition to JNK1, the activation of MEK5-ERK5 MAPK pathway probably plays a pivotal role in transcriptional regulation of AP-1-mediated SPRR1B expression in the distal bronchiolar region. ..
  24. Weldon C, Scandurro A, Rolfe K, Clayton J, Elliott S, Butler N, et al. 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 pubmed
    ..Molecular inhibition of MEK5 signaling may represent a mechanism for sensitizing cancer cells to chemotherapeutic regimens. ..
  25. Villa Moruzzi E. Targeting of FAK Ser910 by ERK5 and PP1delta in non-stimulated and phorbol ester-stimulated cells. Biochem J. 2007;408:7-18 pubmed
    ..The present study indicates, for the first time, the phosphorylation of Ser910 of FAK by ERK5 and its dephosphorylation by PP1d, and suggested a role for Ser910 in the control of cell shape and proliferation. ..
  26. Esparís Ogando A, Diaz Rodriguez E, Montero J, 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 pubmed
  27. Zhou G, Bao Z, Dixon J. Components of a new human protein kinase signal transduction pathway. J Biol Chem. 1995;270:12665-9 pubmed
    ..Both MEK5 and ERK5 are expressed in many adult tissue and are abundant in heart and skeletal muscle. A recombinant GST-ERK5 kinase domain displays autophosphorylation on Ser/Thr and Tyr residues. ..
  28. Kato Y, Zhao M, Morikawa A, Sugiyama T, Chakravortty D, Koide N, et al. Big mitogen-activated kinase regulates multiple members of the MEF2 protein family. J Biol Chem. 2000;275:18534-40 pubmed
    ..Taken together, these data demonstrate that, upon growth factor induction, BMK1 directly phosphorylates and activates three members of the MEF2 family of transcription factors thereby inducing MEF2-dependent gene expression. ..
  29. Wang Y, Su B, Xia Z. Brain-derived neurotrophic factor activates ERK5 in cortical neurons via a Rap1-MEKK2 signaling cascade. J Biol Chem. 2006;281:35965-74 pubmed
    ..This study identifies Rap1 and MEKK2 as critical upstream signaling molecules mediating BDNF stimulation of ERK5 in central nervous system neurons. ..
  30. Abe J, Kusuhara M, Ulevitch R, Berk B, Lee J. Big mitogen-activated protein kinase 1 (BMK1) is a redox-sensitive kinase. J Biol Chem. 1996;271:16586-90 pubmed
    ..These findings demonstrate that activation of BMK1 is different from ERK1/2 and suggest an important role for BMK1 as a redox-sensitive kinase. ..
  31. Nakaoka Y, Nishida K, Fujio Y, Izumi M, Terai K, Oshima Y, et al. Activation of gp130 transduces hypertrophic signal through interaction of scaffolding/docking protein Gab1 with tyrosine phosphatase SHP2 in cardiomyocytes. Circ Res. 2003;93:221-9 pubmed
    ..Taken together, these findings indicate that Gab1-SHP2 interaction plays a crucial role in gp130-dependent longitudinal elongation of cardiomyoctes through activation of ERK5. ..
  32. Hayashi M, Fearns C, Eliceiri B, Yang Y, Lee J. Big mitogen-activated protein kinase 1/extracellular signal-regulated kinase 5 signaling pathway is essential for tumor-associated angiogenesis. Cancer Res. 2005;65:7699-706 pubmed
  33. Dinev D, Jordan B, Neufeld B, Lee J, Lindemann D, Rapp U, et al. Extracellular signal regulated kinase 5 (ERK5) is required for the differentiation of muscle cells. EMBO Rep. 2001;2:829-34 pubmed
    ..Moreover, myogenic differentiation is completely blocked when ERK5 expression is inhibited by antisense RNA. Thus, we conclude that the MEK5/ERK5 MAP kinase cascade is critical for early steps of muscle cell differentiation. ..
  34. Sohn S, Li D, Lee L, Winoto A. Transcriptional regulation of tissue-specific genes by the ERK5 mitogen-activated protein kinase. Mol Cell Biol. 2005;25:8553-66 pubmed
    ..Thus, through its kinase and transcriptional activation domains, ERK5 regulates transcriptional responses of cell survival and quiescence critical for angiogenesis and T-cell function. ..
  35. Regan C, Li W, Boucher D, Spatz S, Su M, Kuida K. Erk5 null mice display multiple extraembryonic vascular and embryonic cardiovascular defects. Proc Natl Acad Sci U S A. 2002;99:9248-53 pubmed
    ..Moreover, the inability of Erk5-deficient mice to form a complex vasculature suggests that Erk5 may play an important role in controlling angiogenesis. ..
  36. Lee J, Ulevitch R, Han J. Primary structure of BMK1: a new mammalian map kinase. Biochem Biophys Res Commun. 1995;213:715-24 pubmed
    ..This suggests BMK1 may regulate signaling events distinct from those controlled by the ERK group of enzymes. ..
  37. Carvajal Vergara X, Tabera S, Montero J, Esparís Ogando A, López Pérez R, Mateo G, et al. Multifunctional role of Erk5 in multiple myeloma. Blood. 2005;105:4492-9 pubmed
    ..These results place the Erk5 route as a new regulatory signaling pathway that affects multiple myeloma proliferation and apoptosis. ..
  38. Mulloy R, Salinas S, Philips A, Hipskind R. Activation of cyclin D1 expression by the ERK5 cascade. Oncogene. 2003;22:5387-98 pubmed
    ..These data identify the cyclin D1 gene as a novel target of the ERK5 cascade, an observation with important implications in cancers involving cyclin D1 deregulation. ..
  39. Li Z, Li J, Mo B, Hu C, Liu H, Qi H, et al. Genistein induces cell apoptosis in MDA-MB-231 breast cancer cells via the mitogen-activated protein kinase pathway. Toxicol In Vitro. 2008;22:1749-53 pubmed publisher
    ..In conclusion, inhibition of the MEK5/ERK5/NF-kappaB pathway may be an important mechanism by which genistein suppresses cell growth and induces apoptosis. ..
  40. Kamakura S, Moriguchi T, Nishida E. Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. Identification and characterization of a signaling pathway to the nucleus. J Biol Chem. 1999;274:26563-71 pubmed
    ..These results reveal a novel signaling pathway to the nucleus mediated by ERK5 that functions downstream of receptor tyrosine kinases to induce immediate early genes, in parallel with the classical MAPK cascade. ..
  41. Sun W, Kesavan K, Schaefer B, Garrington T, Ware M, Johnson N, et al. MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway. J Biol Chem. 2001;276:5093-100 pubmed
    ..MEKK2 and MEKK3 are differentially associated with signaling from specific upstream receptor systems, whereas both activate the MEK5-BMK1/ERK5 pathway. ..
  42. Arnoux V, Nassour M, L Helgoualc h A, Hipskind R, Savagner P. Erk5 controls Slug expression and keratinocyte activation during wound healing. Mol Biol Cell. 2008;19:4738-49 pubmed publisher
    ..Accordingly, they displayed an altered ability to form cell aggregates. These results implicate a novel EGFR/Erk5/Slug pathway in the control of cytoskeleton organization and cell motility in keratinocytes treated with EGF. ..
  43. Zhao M, Liu Y, Bao M, Kato Y, Han J, Eaton J. Vascular smooth muscle cell proliferation requires both p38 and BMK1 MAP kinases. Arch Biochem Biophys. 2002;400:199-207 pubmed
    ..These results may have implications for the future design of pharmacologic agents for inhibition of VSMC growth. ..
  44. Wang X, Merritt A, Seyfried J, Guo C, Papadakis E, Finegan K, et al. Targeted deletion of mek5 causes early embryonic death and defects in the extracellular signal-regulated kinase 5/myocyte enhancer factor 2 cell survival pathway. Mol Cell Biol. 2005;25:336-45 pubmed
    ..Overall, this is the first study to rigorously establish the role of MEK5 in vivo as an activator of ERK5 and as an essential regulator of cell survival that is required for normal embryonic development. ..
  45. Cameron S, Malik S, Akaike M, Lerner Marmarosh N, Yan C, Lee J, et al. Regulation of epidermal growth factor-induced connexin 43 gap junction communication by big mitogen-activated protein kinase1/ERK5 but not ERK1/2 kinase activation. J Biol Chem. 2003;278:18682-8 pubmed
    ..These data indicate that BMK1 is more important than ERK1/2 in EGF-mediated Cx43 gap junction uncoupling by association and Cx43 Ser- 255 phosphorylation. ..
  46. Zhou C, Nitschke A, Xiong W, Zhang Q, Tang Y, Bloch M, et al. 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 pubmed publisher
    ..We further demonstrate that MEK5-mediated progression to an EMT phenotype is dependent upon intact Erk5 and associated with upregulation of SNAI2 and ZEB1 expression. ..
  47. Liu G, Miyata K, Hitomi H, Yao L, Sun G, Suzaki Y, et al. Involvement of mineralocorticoid receptor in high glucose-induced big mitogen-activated protein kinase 1 activation and mesangial cell proliferation. J Hypertens. 2010;28:536-42 pubmed publisher
    ..The inhibitory actions of mineralocorticoid receptor antagonists may contribute to their preventive effects on diabetic nephropathy, which have been reported in recent clinical studies. ..
  48. Fujii Y, Matsuda S, Takayama G, Koyasu S. ERK5 is involved in TCR-induced apoptosis through the modification of Nur77. Genes Cells. 2008;13:411-9 pubmed publisher
    ..Furthermore, the blockade of ERK5 signaling pathway suppressed TCR-induced cell death. These results indicate that ERK5 regulates Nur77 function through its phosphorylation. ..
  49. Katsura H, Obata K, Mizushima T, Sakurai J, Kobayashi K, Yamanaka H, et al. Activation of extracellular signal-regulated protein kinases 5 in primary afferent neurons contributes to heat and cold hyperalgesia after inflammation. J Neurochem. 2007;102:1614-1624 pubmed publisher
    ..Our results show that ERK5 activated in DRG neurons contribute to the development of inflammatory pain. Thus, blocking ERK5 signaling in sensory neurons that has the potential for preventing pain after inflammation. ..
  50. Takeishi Y, Huang Q, Wang T, Glassman M, Yoshizumi M, Baines C, et al. Src family kinase and adenosine differentially regulate multiple MAP kinases in ischemic myocardium: modulation of MAP kinases activation by ischemic preconditioning. J Mol Cell Cardiol. 2001;33:1989-2005 pubmed
    ..These data suggest important roles for Src family kinases and adenosine in mediating preconditioning, and suggest specific roles for individual MAP kinases in preconditioning. ..
  51. Ren X, Ma X, Li Y. All-trans retinoic acid regulates c-jun expression via ERK5 in cardiac myoblasts. J Nutr Biochem. 2007;18:832-8 pubmed
    ..Furthermore, atRA promoted the nuclear translocation of ERK5 but not ERK1. These results suggest that ERK5 pathway may be involved in the process that atRA regulates proliferation in the developing heart. ..
  52. Yan L, Carr J, Ashby P, Murry Tait V, Thompson C, Arthur J. Knockout of ERK5 causes multiple defects in placental and embryonic development. BMC Dev Biol. 2003;3:11 pubmed
    ..Erk5 is essential for early embryonic development, and is required for normal development of the vascular system and cell survival. ..
  53. Villarreal G, Zhang Y, Larman H, Gracia Sancho J, Koo A, Garcia Cardena G. Defining the regulation of KLF4 expression and its downstream transcriptional targets in vascular endothelial cells. Biochem Biophys Res Commun. 2010;391:984-9 pubmed publisher
    ..Collectively, our data identify a significant degree of mechanistic and functional conservation between KLF2 and KLF4, and importantly, provide further insights into the complex regulatory networks governing endothelial vasoprotection. ..