title: Role of phosphatidylinositol 3,4,5-trisphosphate (PIP3) 5-phosphatase skeletal muscle- and kidney-enriched inositol polyphosphate phosphatase (SKIP) in myoblast differentiation.
abstract: Insulin-like growth factors (IGFs) are essential for the development, regeneration, and hypertrophy of skeletal muscles. IGF-II promotes myoblast differentiation through phosphatidylinositol 3-kinase (PI 3-kinase), Akt, and mTOR signaling. Here, we report that skeletal muscle- and kidney-enriched inositol polyphosphate phosphatase (SKIP) negatively regulates myogenesis through inhibition of IGF-II production and attenuation of the IGF-II-Akt-mTOR signaling pathway. We also demonstrate that SKIP expression, which was markedly elevated during differentiation, was controlled by MyoD in C2C12 cells. Expression of SKIP inhibited IGF-II at the transcription level. These results indicate that SKIP regulates MyoD-mediated muscle differentiation. Silencing of SKIP increased IGF-II transcription and myoblast differentiation. Furthermore, knockdown of SKIP resulted in thick myotubes with a larger number of nuclei than that in control C2C12 cells. Taken together, these data indicate that SKIP controls the IGF-II-PI 3-kinase-Akt-mTOR auto-regulation loop during myogenesis. Our findings identify SKIP as a key regulator of muscle cell differentiation.
authors: Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors: Takeshi
authors: T
authors: Ijuin
authors: Tadaomi
authors: T
authors: Takenawa
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D055785:Gene Knockdown Techniques; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D051379:Mice; D024510:Muscle Development / Q000502:physiology*; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000201:enzymology*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C035170:IGF2 protein, human; C513121:IGF2 protein, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D007335:Insulin-Like Growth Factor II; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C531212:Pps protein, mouse; C471548:SKIP enzyme, human; D010744:Phosphoric Monoester Hydrolases