Extracellular signal regulated kinase 5 (ERK5) is required for the differentiation of muscle cells

Dinev, Dragomir; Jordan, Bruce W.M.; Neufeld, Bernd; Lee, Jiing-Dwan; Lindemann, Dirk; Rapp, Ulf R.; Ludwig, Stephan

doi:10.1093/embo-reports/kve177

Cited by 103 publications

(81 citation statements)

References 23 publications

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“…We and others have observed that ERK5 is active during the differentiation of C2C12 myoblasts into myotubes (36). ERK2 activity is also elevated during the end stages of differentiation (37,38).…”

Section: Resultsmentioning

confidence: 54%

Cell Condition-dependent Regulation of ERK5 by cAMP

Pearson

Cobb²

2002

Journal of Biological Chemistry

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ERK5 activity is increased by agents known to activate receptor tyrosine kinases, G-protein coupled receptors, and stress response pathways. We now find a role for cAMP in the regulation of ERK5. ERK5 is activated by forskolin, isoproterenol, and epinephrine in NIH3T3 cells and C2C12 myoblasts. ERK1/2 are also activated by cAMP in NIH3T3 cells, but not in C2C12 myoblasts, demonstrating differential regulation of ERK5 and ERK1/2 by cAMP. We examined the effect of cell context on activation of ERK5 and discovered ERK5 activity is inhibited, rather than activated, by cAMP in confluent, serum-deprived NIH3T3 cells and C2C12 myoblasts. Our results suggest that regulation of MAP kinase pathways by cAMP is not only dictated by cell type, but also by cell context.The transmission of extracellular stimuli into intracellular responses often involves the activation MAP 1 kinase cascades (1, 2). These cascades contain three protein kinases acting in series, a MAP kinase kinase kinase (MAP3K or MEKK) which activates MAP/ERK kinases (MAP2Ks or MEKs), which phosphorylate MAP kinases. Upon activation, MAP kinases regulate cellular responses through the phosphorylation of other protein kinases, cytoplasmic-and membrane-bound proteins, and transcription factors. One of these MAP kinase cascades includes the MAP kinase ERK5 and its upstream activator MEK5. The currently known MAP3Ks that activate MEK5 are MEKK2 and MEKK3 (3, 4).MEK5-ERK5 signaling is involved in the regulation of cellular proliferation. A constitutively active variant of MEK5, MEK5DD, enhances focus formation induced by activated alleles of Raf-1 and MEK1 in NIH3T3 cells (5). ERK5 activity is required for proliferation induced by EGF and granulocyte colony-stimulating factor (6, 7) and focus formation resulting from the expression of an active mutant of Raf (5). ERK5 most likely regulates proliferative responses through the activation of downstream effectors, such as MEF2A, MEF2C, and MEF2D (8), p90 ribosomal S6 kinase (p90RSK), nuclear factor-B (NF-B) (9), and serum-and glucocorticoid-inducible kinase (SGK) (10).While cAMP mediates the trophic actions of hormones that control endocrine gland function, including the thyroid, adrenal cortex, and reproductive organs (11), cAMP inhibits the proliferation of fibroblasts. Changes in MAP kinase activity are often part of the repertoire of events required for cAMP to induce the desired cellular response. For example, ERK1/2 activity is increased by cAMP, and this activation is required for cAMP-stimulated neurite outgrowth in PC12 cells (12, 13). ERK1/2 activation is also thought be involved in cAMP-induced long term potentiation (LTP) (14, 15). The ability of cAMP to inhibit proliferation has often been attributed to a correlative cAMP-dependent protein kinase (PKA)-dependent inhibition of growth factor-stimulated activation of ERK1/2 (16 -18). It has been proposed that the variety of effects of cAMP on MAP kinase activity are derived from differences characteristic to different cell types (12, 13, 16 -21).We tested the...

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Section: Resultsmentioning

confidence: 54%

Cell Condition-dependent Regulation of ERK5 by cAMP

Pearson

Cobb²

2002

Journal of Biological Chemistry

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“…An expression vector for human KLF4 was purchased from Origene and subcloned by EcoRI digest into pBabe puro. pEGZ expression vectors for wild-type human FLAG-Erk5 and dominant-negative flag-Erk5-AEF have been described before (17). For retroviral expression of small hairpin RNA (shRNA) against Erk5, a 64-mer DNA oligonucleotide containing the specific 19-mer targeting sequence GAGTCACCTGATGTCAACC for human and mouse Erk5 was cloned into the BamHI/HindIII sites of the pRetro Super puro (pRS) shRNA expression vector (18).…”

Section: Methodsmentioning

confidence: 99%

Erk5 Activation Elicits a Vasoprotective Endothelial Phenotype via Induction of Krüppel-like Factor 4 (KLF4)

Ohnesorge

Viemann

Schmidt

et al. 2010

Journal of Biological Chemistry

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128

135

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The MEK5/Erk5 MAPK cascade has recently been implicated in the regulation of endothelial integrity and represents a candidate pathway mediating the beneficial effects of laminar flow, a major factor preventing vascular dysfunction and disease. Here we expressed a constitutively active mutant of MEK5 (MEK5D) to study the transcriptional and functional responses to Erk5 activation in human primary endothelial cells. We provide evidence that constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential. This is supported by bioinformatic microarray analysis, which uncovered a statistical overrepresentation of corresponding functional clusters as well as a significant induction of anti-thrombotic, hemostatic, and vasodilatory genes. We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5. We show that KLF4 expression largely reproduces the protective phenotype in endothelial cells, whereas KLF4 siRNA suppresses expression of various Erk5 targets. Additionally, we show that vasoprotective statins potently induce KLF4 and KLF4-dependent gene expression via activation of Erk5. Our data underscore a major protective function of the MEK5/Erk5/KLF4 module in ECs and implicate agonistic Erk5 activation as potential strategy for treatment of vascular diseases.The vascular endothelium, located at the interface between blood and tissue, fulfills a plethora of important functions, including the supply of nutrients and oxygen to the surrounding tissues as well as regulation of hemostasis and inflammatory responses. Endothelial dysfunction contributes to several diseases including chronic inflammation, hemophilia, thrombosis, and atherosclerosis. Thus, elucidation of the factors and molecular mechanisms that influence endothelial function is essential for the development of novel prophylactic and therapeutic strategies against diseases involving the vascular system. A major determinant influencing endothelial integrity is the hemodynamic force exerted by steady pulsatile blood flow. This force generates a continuous shear stress on the endothelial cells (ECs) 3 in the vessel wall, resulting in gene expression changes that protect the vessel from excessive inflammatory responses and thrombosis and provides an essential survival and quiescence signal for the vascular endothelium (1).Various signaling pathways and transcription factors are involved in perception and mediation of shear stress responses. These include the MEK5/Erk5 mitogen-activated protein kinase (MAPK) pathway (2), which is activated by laminar shear stress in ECs (3). In analogy to the related Erk1/2 MAPK, Erk5 activation is triggered by dual phosphorylation at a TEY consensus motif by a mitogen-activated protein kinase kinase (MAPKK or MEK), which in turn is activated via phosphorylation by a MEK kinase (MEKK or MAP3K) (4). In the case of Erk5, the activating phosphorylation is e...

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“…7A-D). Activation of ERK5 has been previously shown to regulate the differentiation of myoblasts (Dinev et al, 2001), by regulating the pro-myogenic actions of IGF-2 (insulin-like growth factor 2) (Carter et al, 2009), suggesting that ERK5 regulates the differentiation of a number of cell types.…”

Section: Discussionmentioning

confidence: 99%

ERK5 is required for VEGF-mediated survival and tubular morphogenesis of primary human microvascular endothelial cells

Roberts

Holmes

Müller

et al. 2010

Journal of Cell Science

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Extracellular signal-regulated kinase 5 (ERK5) is activated in response to environmental stress and growth factors. Gene ablation of Erk5 in mice is embryonically lethal as a result of disruption of cardiovascular development and vascular integrity. We investigated vascular endothelial growth factor (VEGF)-mediated ERK5 activation in primary human dermal microvascular endothelial cells (HDMECs) undergoing proliferation on a gelatin matrix, and tubular morphogenesis within a collagen gel matrix. VEGF induced sustained ERK5 activation on both matrices. However, manipulation of ERK5 activity by siRNA-mediated gene silencing disrupted tubular morphogenesis without impacting proliferation. Overexpression of constitutively active MEK5 and ERK5 stimulated tubular morphogenesis in the absence of VEGF. Analysis of intracellular signalling revealed that ERK5 regulated AKT phosphorylation. On a collagen gel, ERK5 regulated VEGF-mediated phosphorylation of the pro-apoptotic protein BAD and increased expression of the anti-apoptotic protein BCL2, resulting in decreased caspase-3 activity and apoptosis suppression. Our findings suggest that ERK5 is required for AKT phosphorylation and cell survival and is crucial for endothelial cell differentiation in response to VEGF.

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Extracellular signal regulated kinase 5 (ERK5) is required for the differentiation of muscle cells

Cited by 103 publications

References 23 publications

Cell Condition-dependent Regulation of ERK5 by cAMP

Cell Condition-dependent Regulation of ERK5 by cAMP

Erk5 Activation Elicits a Vasoprotective Endothelial Phenotype via Induction of Krüppel-like Factor 4 (KLF4)

ERK5 is required for VEGF-mediated survival and tubular morphogenesis of primary human microvascular endothelial cells

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