title: Src mediates the mechanical activation of myogenesis by activating TNFα-converting enzyme.
abstract: Mechanical stimulation affects many biological aspects in living cells through mechanotransduction. In myogenic precursor cells (MPCs), mechanical stimulation activates p38 mitogen-activated protein kinase (MAPK), a key regulator of myogenesis, via activating TNFα-converting enzyme (TACE, also known as ADAM17), to release autocrine TNFα. However, the signaling mechanism of mechanical activation of TACE is unknown. Because TACE possesses the structural features of substrates of the non-receptor tyrosine kinase Src, we tested the hypothesis that Src mediates mechanical activation of TACE in MPCs. We observed that mechanical stretch of C2C12 or primary rat myoblasts rapidly activates Src, which in turn interacts and colocalizes with TACE, resulting in tyrosine phosphorylation and activation of TACE. Particularly, Src activates TACE via the phosphorylation of amino acid residue Tyr702 in the intracellular tail of TACE, resulting in increased TNFα release and p38 activation. Src inhibition or deficiency blocks stretch activation of the TACE-p38-MAPK signaling, resulting in impaired myogenic gene expression. In response to functional overloading, Src and TACE are activated in mouse soleus muscle. Further, overloading-induced myogenesis and regeneration are impaired in the soleus of Src(+/-) mice. Therefore, Src mediates mechano-activation of TACE and myogenesis.
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX 77030, USA.
authors.forename: Airu
authors.initials: A
authors.lastname: Niu
authors.forename: Yefei
authors.initials: Y
authors.lastname: Wen
authors.forename: Huijie
authors.initials: H
authors.lastname: Liu
authors.forename: Mei
authors.initials: M
authors.lastname: Zhan
authors.forename: Bingwen
authors.initials: B
authors.lastname: Jin
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Li
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D004789:Enzyme Activation; D015870:Gene Expression; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024510:Muscle Development / Q000502:physiology*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; C000606464:Adam17 protein, rat
keywords: ADAM17; Mechanotransduction; Muscle regeneration; Myogenic gene expression; Src; TACE; p38 MAPK