Genomes and Genes
map kinase kinase 5
Summary: A mitogen-activated protein kinase kinase with specificity for MITOGEN-ACTIVATED PROTEIN KINASE 7.
- English J, Vanderbilt C, Xu S, Marcus S, Cobb M. Isolation of MEK5 and differential expression of alternatively spliced forms. J Biol Chem. 1995;270:28897-902 pubmed
- Ramsay A, McCracken S, Soofi M, Fleming J, Yu A, Ahmad I, et al. ERK5 signalling in prostate cancer promotes an invasive phenotype. Br J Cancer. 2011;104:664-72 pubmed publisher..013 and P<0.0001, respectively). Our in vitro, in vivo and clinical data support an important role for the MEK5-ERK5 signalling pathway in invasive PCa, which represents a potential target for therapy in primary and metastatic PCa. ..
- 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. ..
- Winkelmann J, Schormair B, Lichtner P, Ripke S, Xiong L, Jalilzadeh S, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet. 2007;39:1000-6 pubmed..MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder. ..
- Yang Q, Lee J. Targeting the BMK1 MAP kinase pathway in cancer therapy. Clin Cancer Res. 2011;17:3527-32 pubmed publisher..On the other hand, MEK5 inhibitors, BIX02188, BIX02189, and compound 6, suppress cellular MEK5 activity, but no data exist to date on their effectiveness in animals. ..
- Carter E, Cosgrove R, Gonzalez I, Eisemann J, Lovett F, Cobb L, et al. MEK5 and ERK5 are mediators of the pro-myogenic actions of IGF-2. J Cell Sci. 2009;122:3104-12 pubmed publisher..Our findings suggest that the MEK5-ERK5 pathway is a novel key mediator of IGF-2 action in myoblast differentiation. ..
- 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. ..
- 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 pubmed..These results reveal the mechanism by which the activating phosphorylation of ERK5 induces its nuclear import and suggest a novel example of a phosphorylation-dependent control mechanism for nucleocytoplasmic shuttling of proteins. ..
- Ghosh A, Steele R, Ray R. c-myc Promoter-binding protein 1 (MBP-1) regulates prostate cancer cell growth by inhibiting MAPK pathway. J Biol Chem. 2005;280:14325-30 pubmed..Together, our results suggested a novel role of MBP-1 for suppression of prostate cancer cell growth by regulating the MEK5-mediated signaling pathway. ..
- 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. ..
- 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. ..
- 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. ..
- 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. ..
- Ramos Nino M, Blumen S, Sabo Attwood T, Pass H, Carbone M, Testa J, et al. HGF mediates cell proliferation of human mesothelioma cells through a PI3K/MEK5/Fra-1 pathway. Am J Respir Cell Mol Biol. 2008;38:209-17 pubmed..Data suggest that HGF-induced effects in some MM cells are mediated via activation of a novel PI3K/ERK5/Fra-1 feedback pathway that might explain tumor-specific effects of c-Met inhibitors on MM and other tumors. ..
- Nakamura K, Uhlik M, Johnson N, Hahn K, Johnson G. PB1 domain-dependent signaling complex is required for extracellular signal-regulated kinase 5 activation. Mol Cell Biol. 2006;26:2065-79 pubmed..The MEK5 PB1 domain confers stringent MAP3K regulation of ERK5 relative to more promiscuous MAP3K control of ERK1/2, JNK, and p38. ..
- 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. ..
- Tatake R, O Neill M, Kennedy C, Wayne A, Jakes S, Wu D, et al. Identification of pharmacological inhibitors of the MEK5/ERK5 pathway. Biochem Biophys Res Commun. 2008;377:120-5 pubmed publisher..These inhibitors offer novel pharmacological tools to better characterize the role of the MEK5/ERK5 pathway in various biological systems. ..
- 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. ..
- 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. ..
- Drew B, Burow M, Beckman B. MEK5/ERK5 pathway: the first fifteen years. Biochim Biophys Acta. 2012;1825:37-48 pubmed publisher..Further study of this pathway may lead to new prognostic factors and new drug targets to combat more aggressive forms of cancer. ..
- Clark P, Jensen T, Kluger M, Morelock M, Hanidu A, Qi Z, et al. MEK5 is activated by shear stress, activates ERK5 and induces KLF4 to modulate TNF responses in human dermal microvascular endothelial cells. Microcirculation. 2011;18:102-17 pubmed publisher..MEK5/CA-transduced HDMECs are less responsive to TNF, an effect partly mediated by KLF4. MEK5 activation by LSS inhibits inflammatory responses in microvascular ECs, in part through ERK5-dependent induction of KLF4. ..
- Nakamura K, Johnson G. 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 pubmed
- Berwick D, Calissano M, Corness J, Cook S, Latchman D. Regulation of Brn-3a N-terminal transcriptional activity by MEK1/2-ERK1/2 signalling in neural differentiation. Brain Res. 2009;1256:8-18 pubmed publisher..These results reveal an important role for the ERK1/2 pathway in Brn-3a regulation during RA-mediated neuronal differentiation and define the neuropeptide Galanin as a novel target of this transcription factor. ..
- Qu Y, Fang M, Gao B, Amouzadeh H, Li N, Narayanan P, et al. Itraconazole decreases left ventricular contractility in isolated rabbit heart: mechanism of action. Toxicol Appl Pharmacol. 2013;268:113-22 pubmed publisher..The exact mechanism underlying the negative inotropy is uncertain, and requires further study. ..
- Spiering D, Schmolke M, Ohnesorge N, Schmidt M, Goebeler M, Wegener J, et al. MEK5/ERK5 signaling modulates endothelial cell migration and focal contact turnover. J Biol Chem. 2009;284:24972-80 pubmed publisher..We demonstrate for the first time that ERK5 signaling not only is involved in EC survival and stress response but also controls migration and morphology of EC. ..
- Chen L, Kuo W, Yang J, Wang S, Yeh Y, Tsai F, et al. Eccentric cardiac hypertrophy was induced by long-term intermittent hypoxia in rats. Exp Physiol. 2007;92:409-16 pubmed
- 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 pubmed..The nuclear localization of MEK5 and ERK5 is different from that of ERK1/2 and MEK1/2 in resting cells, indicating that each MAPK cascade uses distinct mechanisms to transmit extracellular signals to their nuclear targets. ..
- Razumovskaya E, Sun J, Ronnstrand L. Inhibition of MEK5 by BIX02188 induces apoptosis in cells expressing the oncogenic mutant FLT3-ITD. Biochem Biophys Res Commun. 2011;412:307-12 pubmed publisher..These results suggest that MEK5/ERK5 is important for FLT3-ITD induced hematopoietic transformation and may thus represent an alternative therapeutic target in the treatment of FLT3-ITD positive leukemia. ..
- Chayama K, Papst P, Garrington T, Pratt J, Ishizuka T, Webb S, et al. 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 pubmed..These findings suggest that JNK activation by antigen cross-linking is dependent on the MEKK2-MKK7 pathway, and cytokine production in mast cells is regulated in part by the signaling complex MEKK2-MEK5-ERK5. ..
- García Hoz C, Sánchez Fernández G, Diaz Meco M, Moscat J, Mayor F, Ribas C. G alpha(q) acts as an adaptor protein in protein kinase C zeta (PKCzeta)-mediated ERK5 activation by G protein-coupled receptors (GPCR). J Biol Chem. 2010;285:13480-9 pubmed publisher..These data put forward a novel function of G alpha(q) as a scaffold protein involved in the modulation of the ERK5 cascade by GPCR that could be relevant in G(q)-mediated physiological functions. ..
- Doebele R, Schulze Hoepfner F, Hong J, Chlenski A, Zeitlin B, Goel K, et al. A novel interplay between Epac/Rap1 and mitogen-activated protein kinase kinase 5/extracellular signal-regulated kinase 5 (MEK5/ERK5) regulates thrombospondin to control angiogenesis. Blood. 2009;114:4592-600 pubmed publisher
- Xu B, Stippec S, Lenertz L, Lee B, Zhang W, Lee Y, et al. WNK1 activates ERK5 by an MEKK2/3-dependent mechanism. J Biol Chem. 2004;279:7826-31 pubmed..Finally, ERK5 activation by epidermal growth factor was attenuated by suppression of WNK1 expression using small interfering RNA. Taken together, these results place WNK1 in the ERK5 MAP kinase pathway upstream of MEKK2/3. ..
- Hii C, Anson D, Costabile M, Mukaro V, Dunning K, Ferrante A. Characterization of the MEK5-ERK5 module in human neutrophils and its relationship to ERK1/ERK2 in the chemotactic response. J Biol Chem. 2004;279:49825-34 pubmed..Our data suggest that the MEK5-ERK5 module is likely to regulate neutrophil responses at very low chemoattractant concentrations whereas at higher concentrations, a shift to the ERK1/ERK2 and p38 modules is apparent. ..
- Wang X, McGowan C, Zhao M, He L, Downey J, Fearns C, et al. Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest. Mol Cell Biol. 2000;20:4543-52 pubmed
- Lochhead P, Gilley R, Cook S. ERK5 and its role in tumour development. Biochem Soc Trans. 2012;40:251-6 pubmed publisher..Together, these finding underscore the case for further investigation into understanding the role of ERK5 in cancer. ..
- Izawa Y, Yoshizumi M, Ishizawa K, Fujita Y, Kondo S, Kagami S, et al. Big mitogen-activated protein kinase 1 (BMK1)/extracellular signal regulated kinase 5 (ERK5) is involved in platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell migration. Hypertens Res. 2007;30:1107-17 pubmed publisher..From these findings, it is suggested that BMK1 activation leads to VSMC migration induced by PDGF via Gab1-SHP-2 interaction, and that BMK1-mediated VSMC migration may play a role in the pathogenesis of vascular remodeling. ..
- Pan Y, Zou J, Wang W, Sakagami H, Garelick M, Abel G, et al. Inducible and conditional deletion of extracellular signal-regulated kinase 5 disrupts adult hippocampal neurogenesis. J Biol Chem. 2012;287:23306-17 pubmed publisher..These data suggest ERK5 signaling as a critical regulator of adult hippocampal neurogenesis. ..
- Glatz G, Gogl G, Alexa A, Remenyi A. Structural mechanism for the specific assembly and activation of the extracellular signal regulated kinase 5 (ERK5) module. J Biol Chem. 2013;288:8596-609 pubmed publisher..In particular, they suggest how paralogous enzymes with similar catalytic properties could acquire novel signaling roles by merely changing the way they make physical links to other proteins. ..
- Rampoldi L, Zimbello R, Bortoluzzi S, Tiso N, Valle G, Lanfranchi G, et al. Chromosomal localization of four MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5. Cytogenet Cell Genet. 1997;78:301-3 pubmed..Using radiation hybrid mapping, MEK1 was assigned to chromosome 15q22.1 --> q22.33, MEK3 to chromosome 17q11.2, MEK4 to chromosome 17p12, and MEKK5 to chromosome 6q22.33. ..
- Takahashi N, Saito Y, Kuwahara K, Harada M, Tanimoto K, Nakagawa Y, et al. Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes. J Mol Cell Cardiol. 2005;38:185-92 pubmed..These findings indicate that the major pathway responsible for the hypertrophic responses to CT-1 is not JAK-STAT3 pathway nor MEK1-ERK1/2 pathway, but MEK5-ERK5 pathway. ..
- Li L, Tatake R, Natarajan K, Taba Y, Garin G, Tai C, et al. Fluid shear stress inhibits TNF-mediated JNK activation via MEK5-BMK1 in endothelial cells. Biochem Biophys Res Commun. 2008;370:159-63 pubmed publisher..These results support a key role for the MEK5-BMK1 signaling pathway in the atheroprotective effects of blood flow. ..
- Wei X, Sun W, Fan R, Hahn J, Joetham A, Li G, et al. MEF2C regulates c-Jun but not TNF-alpha gene expression in stimulated mast cells. Eur J Immunol. 2003;33:2903-9 pubmed
- Sato Y, Harada K, Kizawa K, Sanzen T, Furubo S, Yasoshima M, et al. Activation of the MEK5/ERK5 cascade is responsible for biliary dysgenesis in a rat model of Caroli's disease. Am J Pathol. 2005;166:49-60 pubmed..As the MEK5-ERK5 interaction is highly specific, it may represent a potential target of therapy. ..
- Wu Y, Feng B, Chen S, Zuo Y, Chakrabarti S. Glucose-induced endothelin-1 expression is regulated by ERK5 in the endothelial cells and retina of diabetic rats. Can J Physiol Pharmacol. 2010;88:607-15 pubmed publisher..These data indicate that ERK5 signaling regulates glucose-induced ET-1 expression in diabetes. The ERK5/ET-1 pathway may provide a potential novel target for the treatment of diabetic angiopathy. ..
- Ren D, Yang H, Zhang S. Cell death mediated by MAPK is associated with hydrogen peroxide production in Arabidopsis. J Biol Chem. 2002;277:559-65 pubmed..As a result, we speculate that the prolonged activation of the MAPK pathway in cells could disrupt the redox balance, which leads to the generation of reactive oxygen species and eventually HR cell death. ..
- 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. ..
- Katsarou K, Tsitoura P, Georgopoulou U. MEK5/ERK5/mef2: a novel signaling pathway affected by hepatitis C virus non-enveloped capsid-like particles. Biochim Biophys Acta. 2011;1813:1854-62 pubmed publisher..These cell signaling events could be of critical importance and might give clues for the elucidation of cellular manifestations associated with HCV infection. ..
- 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. ..
- Dorado F, Velasco S, Esparís Ogando A, Pericacho M, Pandiella A, Silva J, et al. The mitogen-activated protein kinase Erk5 mediates human mesangial cell activation. Nephrol Dial Transplant. 2008;23:3403-11 pubmed publisher..These results suggest that Erk5 is involved in agonist-induced mesangial cell contraction, proliferation and ECM accumulation and point to a multifunctional role of Erk5 in the pathophysiology of glomerular mesangial cells. ..
- Abbasi S, Lee J, Su B, Chen X, Alcon J, Yang J, et al. Protein kinase-mediated regulation of calcineurin through the phosphorylation of modulatory calcineurin-interacting protein 1. J Biol Chem. 2006;281:7717-26 pubmed
- Li J, Li Z, Mo B. [Effects of ERK5 MAPK signaling transduction pathway on the inhibition of genistein to breast cancer cells]. Wei Sheng Yan Jiu. 2006;35:184-6 pubmed..Genistein can affect the ERK5 MAPK signaling transduction pathway and induce the expressions of apoptosis related proteins to inhibit the proliferation of MDA-MB-231 cells. ..
- Zhang G, Wang S. Proteomic approach to substrates related to MAPK pathway in 293T cells. Cell Biol Int. 2007;31:1-10 pubmed..In conclusion, our study not only confirms that MST1, glutathione S-transferase p1-1, glycoprotein IX and soluble PPase belong to MAPK pathways, but also provides seven novel molecules for the further study of the pathways. ..