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Nestor Gomez, Tatiana Erazo, Jose M Lizcano
ERK5, the last MAP kinase family member discovered, is activated by the upstream kinase MEK5 in response to growth factors and stress stimulation. MEK5-ERK5 pathway has been associated to different cellular processes, playing a crucial role in cell proliferation in normal and cancer cells by mechanisms that are both dependent and independent of its kinase activity. Thus, nuclear ERK5 activates transcription factors by either direct phosphorylation or acting as co-activator thanks to a unique transcriptional activation TAD domain located at its C-terminal tail...
2016: Frontiers in Cell and Developmental Biology
Maria Elena Bravo-Adame, Rosario Vera-Estrella, Bronwyn J Barkla, Cecilia Martínez-Campos, Angel Flores-Alcantar, Jose Pablo Ocelotl-Oviedo, Gustavo Pedraza-Alva, Yvonne Rosenstein
CD43 is one of the most abundant co-stimulatory molecules on a T-cell surface; it transduces activation signals through its cytoplasmic domain, contributing to modulation of the outcome of T-cell responses. The aim of this study was to uncover new signalling pathways regulated by this sialomucin. Analysis of changes in protein abundance allowed us to identify pyruvate kinase isozyme M2 (PKM2), an enzyme of the glycolytic pathway, as an element potentially participating in the signalling cascade resulting from the engagement of CD43 and the T-cell receptor (TCR)...
September 8, 2016: Immunology
Seong Ji Park, Yu Sun Choi, Seungkoo Lee, Young Jae Lee, Suntaek Hong, Sanghwa Han, Byung-Chul Kim
Transforming growth factor-β1 (TGF-β1) promotes tumor metastasis by inducing an epithelial-to-mesenchymal transition (EMT) in cancer cells. In this study, we investigated the effects of BIX02189 and XMD8-92, pharmacologic inhibitors of the MEK5 [mitogen-activated protein kinase/extracellular-signal-regulated kinase (ERK)5] signaling pathway, on the EMT and migration of cancer cells induced by TGF-β1. In human A549 lung cancer cells, TGF-β1-induced EMT, cell motility, and expression of matrix metalloproteinase-2 were completely inhibited by BIX02189, but not by XMD8-92 or small interference RNAs specific to MEK5 and ERK5...
October 28, 2016: Cancer Letters
Joo-Young Im, Sung-Hoon Yoon, Bo-Kyung Kim, Hyun Seung Ban, Kyoung-Jae Won, Kyung-Sook Chung, Kyeong Eun Jung, Misun Won
DNA damage induced apoptosis suppressor (DDIAS) is an anti-apoptotic protein that promotes cancer cell survival. We previously reported that DDIAS is transcriptionally activated by nuclear factor of activated T cells 2 (NFATc1). However, the upstream regulation of DDIAS expression by growth factors has not been studied. Here, we demonstrate that DDIAS expression is induced by extracellular signal-regulated kinase 5 (ERK5) and myocyte enhancer factor 2B (MEF2B) in response to epidermal growth factor (EGF) and that it positively regulates β-catenin signaling in HeLa cells...
July 10, 2016: Biochimica et Biophysica Acta
Maria Tsioumpekou, Natalia Papadopoulos, Fatima Burovic, Carl-Henrik Heldin, Johan Lennartsson
Platelet-derived growth factor-BB (PDGF-BB) binds to its tyrosine kinase receptors (PDGFRs) and stimulates mitogenicity and survival of cells of mesenchymal origin. Activation of PDGFRs initiates a number of downstream signaling pathways, including phosphatidyl 3'-inositol kinase (PI3-kinase), phospholipase Cγ and MAP kinase pathways. In this report, we show that Erk5 MAP kinase is activated in response to PDGF-BB in the smooth muscle cell line MOVAS in a manner dependent on Mekk2, Mek1/2, Mek5, PI3-kinase and protein kinase C (PKC)...
September 2016: Cellular Signalling
André E S Simões, Cecília M P Rodrigues, Pedro M Borralho
Conventional mitogen-activated protein kinase (MAPK) family members are among the most sought-after oncogenic effectors for the development of novel human cancer treatment strategies. MEK5/ERK5 has been the less-studied MAPK subfamily, despite its increasingly demonstrated relevance in the growth, survival, and differentiation of normal cells. MEK5/ERK5 signalling has already been proposed to have pivotal roles in several cancer hallmarks, and to mediate the effects of a range of oncogenes. Accumulating evidence indicates the contribution of MEK5/ERK5 signalling to therapy resistance and the benefits of using MEK5/ERK5 inhibitory strategies in the treatment of human cancer...
June 16, 2016: Drug Discovery Today
Dechang Diao, Lei Wang, Jin Wan, Zhiqiang Chen, Junsheng Peng, Huanliang Liu, Xinlin Chen, Wei Wang, Liaonan Zou
BACKGROUND: Mitogen/extracellular signal-regulated kinase kinase-5 (MEK5) has been confirmed to play a pivotal role in tumor carcinogenesis and progression. However, few studies have investigated the role of MEK5 in colorectal cancer (CRC). METHODS: MEK5 expression was determined by immunohistochemistry (IHC) in tissue microarrays (TMAs) containing 2 groups of tissues, and western blotting was used to confirm MEK5 expression in 8 cases of primary CRC tissues and paired normal mucosa...
2016: BMC Cancer
Diane M Pereira, André E S Simões, Sofia E Gomes, Rui E Castro, Tânia Carvalho, Cecília M P Rodrigues, Pedro M Borralho
The MEK5/ERK5 signaling pathway is emerging as an important contributor to colon cancer onset, progression and metastasis; however, its relevance to chemotherapy resistance remains unknown. Here, we evaluated the impact of the MEK5/ERK5 cascade in colon cancer cell sensitivity to 5-fluorouracil (5-FU). Increased ERK5 expression was correlated with poor overall survival in colon cancer patients. In colon cancer cells, 5-FU exposure impaired endogenous KRAS/MEK5/ERK5 expression and/or activation. In turn, MEK5 constitutive activation reduced 5-FU-induced cytotoxicity...
June 7, 2016: Oncotarget
Pamela A Lochhead, Jonathan Clark, Lan-Zhen Wang, Lesley Gilmour, Matthew Squires, Rebecca Gilley, Caroline Foxton, David R Newell, Stephen R Wedge, Simon J Cook
ERK5, encoded by MAPK7, has been proposed to play a role in cell proliferation, thus attracting interest as a cancer therapeutic target. While oncogenic RAS or BRAF cause sustained activation of the MEK1/2-ERK1/2 pathway, ERK5 is directly activated by MEK5. It has been proposed that RAS and RAF proteins can also promote ERK5 activation. Here we investigated the interplay between RAS-RAF-MEK-ERK and ERK5 signaling and studied the role of ERK5 in tumor cell proliferation in 2 disease-relevant cell models. We demonstrate that although an inducible form of CRAF (CRAF:ER*) can activate ERK5 in fibroblasts, the response is delayed and reflects feed-forward signaling...
2016: Cell Cycle
C Wang, T Zhang, W Liu, H Meng, Y Song, W Wang
Sox9 is a member of the high-mobility-group (HMG) box protein superfamily, which is expressed predominantly among cells in mesenchymal condensations during the early development of embryonic skeletons. The extracellular-signal-regulated kinase 5 (ERK5) is one of the mitogen-activated protein kinase (MAPK) family members of protein kinases. Roles for ERK5 signaling in the regulation of chondrogenesis and adult chondrocyte homeostasis have yet to be demonstrated. In this study, we found that ERK5 could down-regulate Col2al and Sox9 expression, and this down-regulation was inhibited by MEK5β, one of ERK5 inhibitor...
2016: Cellular and Molecular Biology
Mamiko Iwatsuki, Masato Matsuoka
Excessive systemic exposure to fluoride leads to disturbances of bone homeostasis. c-Fos is known to be essential in bone development by affecting osteoblast and osteoclast differentiation. In this study, we examined the effects of fluoride exposure on c-Fos expression and its regulatory signaling pathways in MC3T3-E1 mouse osteoblast cell line. c-fos mRNA level, c-Fos protein level and c-Fos DNA-binding activity were markedly increased, with a peak at 2 or 4 h, in MC3T3-E1 cells exposed to sodium fluoride (NaF)...
February 2016: Toxicology Mechanisms and Methods
Roberto Cuttano, Noemi Rudini, Luca Bravi, Monica Corada, Costanza Giampietro, Eleanna Papa, Marco Francesco Morini, Luigi Maddaluno, Nicolas Baeyens, Ralf H Adams, Mukesh K Jain, Gary K Owens, Martin Schwartz, Maria Grazia Lampugnani, Elisabetta Dejana
Cerebral cavernous malformations (CCMs) are vascular malformations located within the central nervous system often resulting in cerebral hemorrhage. Pharmacological treatment is needed, since current therapy is limited to neurosurgery. Familial CCM is caused by loss-of-function mutations in any of Ccm1, Ccm2, and Ccm3 genes. CCM cavernomas are lined by endothelial cells (ECs) undergoing endothelial-to-mesenchymal transition (EndMT). This switch in phenotype is due to the activation of the transforming growth factor beta/bone morphogenetic protein (TGFβ/BMP) signaling...
January 2016: EMBO Molecular Medicine
Xavier Cullere, Eva Plovie, Paul M Bennett, Calum A MacRae, Tanya N Mayadas
Three genes, CCM1, CCM2, and CCM3, interact genetically and biochemically and are mutated in cerebral cavernous malformations (CCM). A recently described member of this CCM family of proteins, CCM2-like (CCM2L), has high homology to CCM2. Here we show that its relative expression in different tissues differs from that of CCM2 and, unlike CCM2, the expression of CCM2L in endothelial cells is regulated by density, flow, and statins. In vitro, both CCM2L and CCM2 bind MEKK3 in a complex with CCM1. Both CCM2L and CCM2 interfere with MEKK3 activation and its ability to phosphorylate MEK5, a downstream target...
November 17, 2015: Proceedings of the National Academy of Sciences of the United States of America
Kevin Wilhelmsen, Fengyun Xu, Katherine Farrar, Alphonso Tran, Samira Khakpour, Shirin Sundar, Arun Prakash, Jinhua Wang, Nathanael S Gray, Judith Hellman
Inflammatory critical illness is a syndrome that is characterized by acute inflammation and organ injury, and it is triggered by infections and noninfectious tissue injury, both of which activate innate immune receptors and pathways. Although reports suggest an anti-inflammatory role for the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 5 (ERK5), we previously found that ERK5 mediates proinflammatory responses in primary human cells in response to stimulation of Toll-like receptor 2 (TLR2)...
August 25, 2015: Science Signaling
Xavier Rovira-Clavé, Maria Angulo-Ibáñez, Cathy Tournier, Manuel Reina, Enric Espel
Regulation of the levels of the TCR/CD3 complex at the cell surface is critical to proper T cell development and mature T cell activation. We provide evidence that the MAPK ERK5 regulates the surface expression of the TCR/CD3 complex by controlling the degradation of the CD3ζ chain and the recovery of the complex after anti-CD3ε stimulation. ERK5 knockdown led to TCR/CD3 up-regulation at the cell surface and increased amounts of the CD3ζ chain. Inhibition of the MEK5-dependent phosphorylation status of the kinase domain of ERK5 in human T CD4(+) cells reduced CD3ζ ubiquitination and degradation, limiting TCR/CD3 down-regulation in anti-CD3-stimulated cells...
January 2016: Journal of Leukocyte Biology
Jan-Renier A J Moonen, Ee Soo Lee, Marc Schmidt, Monika Maleszewska, Jasper A Koerts, Linda A Brouwer, Theo G van Kooten, Marja J A van Luyn, Clark J Zeebregts, Guido Krenning, Martin C Harmsen
AIMS: Neointimal hyperplasia is a common feature of fibro-proliferative vascular disease and characterizes initial stages of atherosclerosis. Neointimal lesions mainly comprise smooth muscle-like cells. The presence of these lesions is related to local differences in shear stress. Neointimal cells may arise through migration and proliferation of smooth muscle cells from the media. However, a role for the endothelium as a source of smooth muscle-like cells has largely been disregarded...
December 1, 2015: Cardiovascular Research
Mohamed M Hafez, Naif O Al-Harbi, Ali Rashed Al-Hoshani, Khaled A Al-Hosaini, Shakir D Al Shrari, Salim S Al Rejaie, Mohamed M Sayed-Ahmed, Othman A Al-Shabanah
BACKGROUND: Carbon tetrachloride (CCl4) induces hepatotoxicity in animal models, including the increased blood flow and cytokine accumulation that are characteristic of tissue inflammation. The present study investigates the hepato-protective effect of rutin on CCl4-induced hepatotoxicity in rats. RESULTS: Forty male Wistar rats were divided into four groups. Group I (control group) received 1 mL/kg of dimethyl sulfoxide intragastrically and 3 mL/kg olive oil intraperitoneally twice a week for 4 weeks...
2015: Biological Research
Paul R Gavine, Mei Wang, Dehua Yu, Eva Hu, Chunlei Huang, Jenny Xia, Xinying Su, Joan Fan, Tianwei Zhang, Qingqing Ye, Li Zheng, Guanshan Zhu, Ziliang Qian, Qingquan Luo, Ying Yong Hou, Qunsheng Ji
BACKGROUND: MAPK7/ERK5 (extracellular-signal-regulated kinase 5) functions within a canonical three-tiered MAPK (mitogen activated protein kinase) signaling cascade comprising MEK (MAPK/ERK kinase) 5, MEKK(MEK kinase) 2/3 and ERK5 itself. Despite being the least well studied of the MAPK-modules, evidence supports a role for MAPK7-signaling in the pathology of several cancer types. METHODS AND RESULTS: Fluorescence in situ hybridization (FISH) analysis identified MAPK7 gene amplification in 4% (3/74) of non-small cell lung cancers (NSCLC) (enriched to 6% (3/49) in squamous cell carcinoma) and 2% (2/95) of squamous esophageal cancers (sqEC)...
2015: BMC Cancer
Shoichi Kaneshiro, Dai Otsuki, Kiyoshi Yoshida, Hideki Yoshikawa, Chikahisa Higuchi
Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase (MAPK) family and is activated by its upstream kinase, MAPK kinase 5 (MEK5), which is a member of the MEK family. Although the role of MEK5 has been investigated in several fields, little is known about its role in osteoblastic differentiation. In this study, we have demonstrated the role of MEK5 in osteoblastic differentiation in mouse preosteoblastic MC3T3-E1 cells and bone marrow stromal ST2 cells. We found that treatment with BIX02189, an inhibitor of MEK5, increased alkaline phosphatase (ALP) activity and the gene expression of ALP, osteocalcin (OCN) and osterix, as well as it enhanced the calcification of the extracellular matrix...
July 31, 2015: Biochemical and Biophysical Research Communications
Emilie Jacque, Edina Schweighoffer, Victor L J Tybulewicz, Steven C Ley
B cell activating factor (BAFF) stimulation of the BAFF receptor (BAFF-R) is essential for the homeostatic survival of mature B cells. Earlier in vitro experiments with inhibitors that block MEK 1 and 2 suggested that activation of ERK 1 and 2 MAP kinases is required for BAFF-R to promote B cell survival. However, these inhibitors are now known to also inhibit MEK5, which activates the related MAP kinase ERK5. In the present study, we demonstrated that BAFF-induced B cell survival was actually independent of ERK1/2 activation but required ERK5 activation...
June 1, 2015: Journal of Experimental Medicine
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