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Chengli Song, Lina Wang, Qiang Xu, Kai Wang, Dan Xie, Zhe Yu, Kui Jiang, Lujian Liao, John R Yates, Jiing-Dwan Lee, Qingkai Yang
Combined inhibition of BRAF and MEK1/2 (CIBM) improves therapeutic efficacy of BRAF-mutant melanoma. However, drug resistance to CIBM is inevitable and the drug resistance mechanisms still remain to be elucidated. Here, we show that BMK1 pathway contributes to the drug resistance to CIBM. Considering that ERK1/2 pathway regulates cellular processes by phosphorylating, we first performed a SILAC phosphoproteomic profiling of CIBM. Phosphorylation of 239 proteins was identified to be downregulated, while phosphorylation of 47 proteins was upregulated...
April 7, 2017: Scientific Reports
Ting-Huan Chen, Chen-Yu Chen, Hui-Chin Wen, Chia-Chu Chang, Horng-Dar Wang, Chih-Pin Chuu, Chung-Ho Chang
Yes-associated protein (YAP) is a transcriptional coactivator in the Hippo pathway that regulates cell proliferation, differentiation, and apoptosis. The MEK5/ERK5 MAPK cascade is essential for the early step of myogenesis. In this study, we generated C2C12 stable cell lines that expressed YAP (C2C12-YAP cells) and found that ERK5 and MEK5 were activated in C2C12-YAP cells compared with control C2C12 (C2C12-vector) cells. C2C12-YAP stable cells also differentiated into myotubes better than C2C12-vector cells, and expressed elevated levels of myogenin, a transcription factor that regulates myogenesis, as well as elevated levels of myosin heavy chain, a skeletal muscle marker...
March 29, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Mitsunori Miyazaki, Tohru Takemasa
The enhanced rate of protein synthesis in skeletal muscle cells results in a net increase in total protein content that leads to skeletal muscle growth/hypertrophy. The mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)-dependent regulation of the activity of mechanistic target of rapamycin (mTOR) and subsequent protein synthesis has been suggested as a regulatory mechanism; however, the exact molecular processes underlying such a regulation are poorly defined. The purpose of this study was to investigate regulatory mechanisms involved in the MEK/ERK-dependent pathway leading to mTORC1 activation in skeletal muscle cells...
March 2017: FEBS Open Bio
Ning Gu, Keli Ge, Cui Hao, Yaqing Ji, Hongyun Li, Yunliang Guo
Neuregulin1β (NRG1β), a member of the excitomotor of tyrosine kinase receptor (erbB) family, was recently shown to play a neuroprotective role in cerebral ischemia-reperfusion injury. The present study analyzed the effects and its possible signaling pathway of NRG1β on brain tissues after cerebral ischemia-reperfusion injury. A focal cerebral ischemic model was established by inserting a monofilament thread to achieve middle cerebral artery occlusion, followed by an NRG1β injection via the internal carotid artery...
April 2017: Journal of Molecular Neuroscience: MN
Van T Hoang, Thomas J Yan, Jane E Cavanaugh, Patrick T Flaherty, Barbara S Beckman, Matthew E Burow
Mitogen-activated protein kinases (MAPKs) regulate diverse cellular processes including proliferation, cell survival, differentiation, and apoptosis. While conventional MAPK constituents have well-defined roles in oncogenesis, the MEK5 pathway has only recently emerged in cancer research. In this review, we consider the MEK5 signaling cascade, focusing specifically on its involvement in drug resistance and regulation of aggressive cancer phenotypes. Moreover, we explore the role of MEK5/ERK5 in tumorigenesis and metastatic progression, discussing the discrepancies in preclinical studies and assessing its viability as a therapeutic target for anti-cancer agents...
January 30, 2017: Cancer Letters
Ruifang Zheng, George P Studzinski
Cytarabine (AraC) has been the primary treatment agent for acute myeloid leukemia (AML) in the past 30 years, but the precise mechanism of its action is not completely known. Here we assessed the role of ERK5 in AraC-induced cell death in AML cell lines HL60 and U937 using ERK5 inhibitors BIX02189 and XMD8-92. We report that inhibition of MEK5/ERK5 activity reduces AraC-induced cell death, DNA damage, the upregulated DNA damage biomarkers, and produced G2 phase cell cycle arrest. In addition, the pro-survival protein P-Bcl2 Ser70 was found to be associated with decreased AraC-induced cell death following XMD8-92 treatment, suggesting a regulatory role of ERK5 on Bcl2 phosphorylation...
June 2017: Journal of Cellular Biochemistry
Fang Liu, Hao Zhang, Hui Song
Mitogen extracellular-signal-regulated kinase kinase 5 (MEK5) plays an important role in promoting cell proliferation and tumorigenesis. The aberrant expression of MEK5 has been reported in various malignant diseases including cancers of breast, prostate, lung, colorectal and brain. However, the function and regulation of MEK5 signaling pathway are ambiguous and remain elusive with respect to its oncogenic roles in various cancers, especially in the regulation of the initiation and progression of cancer invasion and metastasis...
January 2017: Oncology Reports
Mahesh Appari, Astrid Breitbart, Florian Brandes, Malgorzata Szaroszyk, Natali Froese, Mortimer Korf-Klingebiel, Mona Malek Mohammadi, Andrea Grund, Gesine M Scharf, Honghui Wang, Carolin Zwadlo, Daniela Fraccarollo, Ulrike Schrameck, Mona Nemer, William Wong, Hugo A Katus, Kai C Wollert, Oliver J Müller, Johann Bauersachs, Joerg Heineke
RATIONALE: Myocardial endothelial cells promote cardiomyocyte hypertrophy, possibly through the release of growth factors. The identity of these factors, however, remains largely unknown, and we hypothesized here that the secreted C1q-TNF-related protein-9 (CTRP9) might act as endothelial derived protein to modulate heart remodeling in response to pressure overload. OBJECTIVE: To examine the source of cardiac CTRP9 and its function during pressure overload. METHODS AND RESULTS: CTRP9 was mainly derived from myocardial capillary endothelial cells...
November 7, 2016: Circulation Research
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)...
January 2017: 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...
November 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...
February 4, 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 1, 2016: EMBO Molecular Medicine
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