title: YAP promotes myogenic differentiationviathe MEK5-ERK5 pathway.
abstract: 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. Western blot analysis revealed that Src and c-Abl (Abelson murine leukemia viral oncogene homolog 1) activation were enhanced in C2C12-YAP cells. Conversely, treatment of inhibitors of c-Abl, Src, or MEK5 inhibited activation of MEK5 and ERK5 and myogenesis of C2C12 myoblasts. Specific interactions between YAP and proteins in the ERK5 pathway, such as MEK kinase 3 (MEKK3) and ERK5, were illustrated by coimmunoprecipitation experiments. MEKK3 contains the PPGY motif (aa 178-181), which may interact with YAP. Site-directed mutagenesis experiments revealed that expression of MEKK3 Y181F mutant inhibited MEK5/ERK5 activation and myogenic differentiation. These results suggest that YAP promotes muscle differentiation by activating the Abl/Src/MEKK3/MEK5/ERK5 kinase cascade.-Chen, T.-H., Chen, C.-Y., Wen, H.-C., Chang, C.-C., Wang, H.-D., Chuu, C.-P., Chang, C.-H. YAP promotes myogenic differentiationviathe MEK5-ERK5 pathway.
authors.affiliation: Department of Life Science, National Tsing Hua University, Hsin-Chu, Taiwan, China.|Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan, China.
authors.forename: Ting-Huan
authors.initials: TH
authors.lastname: Chen
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan, China.
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan, China.
authors.forename: Hui-Chin
authors.initials: HC
authors.lastname: Wen
authors.affiliation: Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan, China.
authors.forename: Chia-Chu
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Life Science, National Tsing Hua University, Hsin-Chu, Taiwan, China.
authors.forename: Horng-Dar
authors.initials: HD
authors.lastname: Wang
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan, China; cpchuu@nhri.org.tw.
authors.forename: Chih-Pin
authors.initials: CP
authors.lastname: Chuu
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan, China; changch@nhri.org.tw.|Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan, China.
authors.forename: Chung-Ho
authors.initials: CH
authors.lastname: Chang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002460:Cell Line; D003593:Cytoplasm; D005786:Gene Expression Regulation / Q000502:physiology*; D016313:Genes, abl; D048671:MAP Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D048748:MAP Kinase Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D024510:Muscle Development / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D000091102:YAP-Signaling Proteins; D019061:src-Family Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D019061:src-Family Kinases; D048054:Mitogen-Activated Protein Kinase 7; D048748:MAP Kinase Kinase Kinase 3; C482626:Map3k3 protein, mouse; D048671:MAP Kinase Kinase 5; C578399:Map2k5 protein, mouse
keywords: Abl; C2C12 myoblasts; Src; TAZ; myogenesis