{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:07:21Z","timestamp":1790629641812,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2017,1,30]],"date-time":"2017-01-30T00:00:00Z","timestamp":1485734400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["FEBS Open Bio"],"published-print":{"date-parts":[[2017,3]]},"abstract":"<jats:p>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\u2010activated protein kinase kinase (MEK)\/extracellular signal\u2010regulated kinase (ERK)\u2010dependent 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\u2010dependent pathway leading to mTORC1 activation in skeletal muscle cells. Treatment with phorbol\u201012\u2010myristate\u201013\u2010acetate (PMA), a potent agonist of protein kinase C (PKC) and its downstream effector in the MEK\/ERK\u2010dependent pathway, resulted in the activation of mTORC1 signaling and phosphorylation of the upstream regulator tuberous sclerosis 2 (TSC2) in C2C12 myoblasts. PMA\u2010induced activation of mTORC1 signaling was partially prevented by treatment with U0126 (a selective inhibitor of MEK1\/2) or BIX\u201002189 (a selective inhibitor of MEK5) and completely blocked with BIM\u2010I (a selective inhibitor of upstream PKC). TSC2 phosphorylation at Ser664 (an ERK\u2010dependent phosphorylation site) was prevented with U0126, and BIM\u2010I treatment blocked PMA\u2010induced phosphorylation of TSC2 at multiple residues (Ser664, Ser939, and Thr1462). Overexpression of Ras homolog enriched in brain (Rheb), a downstream target of TSC2, and an mTORC1 activator, was sufficient to activate mTORC1 signaling. We also identified that PMA\u2010induced activation of mTORC1 signaling was significantly inhibited in the absence of Rheb with siRNA knockdown. These observations demonstrate that the PKC\/MEK\/ERK\u2010dependent activation of mTORC1 is mediated through TSC2 phosphorylation and its downstream target Rheb in C2C12 myoblasts.<\/jats:p>","DOI":"10.1002\/2211-5463.12195","type":"journal-article","created":{"date-parts":[[2017,1,11]],"date-time":"2017-01-11T08:12:49Z","timestamp":1484122369000},"page":"424-433","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["TSC2\/Rheb signaling mediates ERK\u2010dependent regulation of mTORC1 activity in C2C12 myoblasts"],"prefix":"10.1002","volume":"7","author":[{"given":"Mitsunori","family":"Miyazaki","sequence":"first","affiliation":[{"name":"Department of Physical Therapy School of Rehabilitation Sciences Health Sciences University of Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tohru","family":"Takemasa","sequence":"additional","affiliation":[{"name":"Graduate School of Comprehensive 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