title: M-cadherin-inhibited phosphorylation of ß-catenin augments differentiation of mouse myoblasts.
abstract: β-Catenin is essential for muscle development because it regulates both cadherin-mediated cell-cell adhesion and canonical Wingless and Int1 (Wnt) signaling. The phosphorylation of β-catenin by glycogen synthase kinase-3β (GSK-3β) at serine31/37/threonine41 regulates its stability and its role in canonical Wnt signaling. In this study, we have investigated whether the N-terminal phosphorylation of β-catenin is regulated by M-cadherin, and whether this regulation mediates the role of M-cadherin in myogenic differentiation. Our data show that the knockdown of M-cadherin expression by RNA interference (RNAi) in C2C12 myoblasts significantly increases the phosphorylation of β-catenin at Ser33/37/Thr41 and decreases the protein abundance of ser37/thr41-unphosphorylated active β-catenin. Furthermore, M-cadherin RNAi promotes TCF/LEF transcription activity but also blunts the initiation of the myogenic progress by Wnt pathway activator lithium chloride or Wnt-3a treatment. Knockdown of β-catenin expression by RNAi decreases myogenic induction in myoblasts. Forced expression of a phosphorylation-resistant β-catenin plasmid (S33Y-β-catenin) fails to enhance myogenic differentiation, but it partially rescues C2C12 cells from M-cadherin RNAi-induced apoptosis. These data show, for the first time, that M-cadherin-mediated signaling attenuates β-catenin phosphorylation at Ser31/37/Thr41 by GSK-3β, and that this regulation has a positive effect on myogenic differentiation induced by canonical Wnt signaling.
authors.affiliation: Laboratory of Muscle Biology and Sarcopenia, Department of Exercise Physiology, and Center for Cardiovascular and Respiratory Sciences, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown, WV 26506, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Junaith S
authors.initials: JS
authors.lastname: Mohamed
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Alway
mesh_terms: D000818:Animals; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism*; D002452:Cell Count; D002454:Cell Differentiation; D002459:Cell Fusion; D015536:Down-Regulation; D005355:Fibrosis; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D024510:Muscle Development; D050505:Mutant Proteins / Q000378:metabolism; D032446:Myoblasts / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D010766:Phosphorylation; D034622:RNA Interference; D013347:Subcellular Fractions / Q000378:metabolism; D051820:TCF Transcription Factors / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D050505:Mutant Proteins; D051820:TCF Transcription Factors; D051176:beta Catenin; C070896:M-cadherin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3