title: Subtilisin-like proprotein convertase PACE4 is required for skeletal muscle differentiation.
abstract: Most growth factors stimulate myoblast proliferation and prevent differentiation, whereas insulin-like growth factors (IGFs) promote myoblast differentiation through the phosphatidylinositol 3-kinase (PI3K) pathway. Subtilisin-like proprotein convertases (SPCs) are involved in cell growth and differentiation via activation of pro-growth factors. However, the role of SPCs in myogenesis remains poorly understood. Here we show that PACE4, a member of the SPC family, plays a critical role in myogenic differentiation of C2C12 cells. PACE4 mRNA levels increased markedly during myogenesis, whereas the expression of other member of SPC family, furin and PC6, remained unchanged. The expression pattern of pro-IGF-II, which is processed extracellularly by SPCs, was similar to that of PACE4. The expression of shRNA targeting PACE4, but not furin, suppressed the expression of the muscle-specific myosin light chain (MLC). Interestingly, reduced expression of MLC was restored following treatment with recombinant mature IGF-II. Finally, we demonstrated that the PI3K inhibitor LY294002 blocked the induction of PACE4 mRNA, a result not observed when another myogenic differentiation inhibitor, SB203580 (p38 MAP kinase inhibitor), was employed, indicating the presence of a positive feedback loop regulating PACE4 expression. These results suggest that PACE4 plays an important role in myogenic differentiation through its association with the IGF-II pathway.
authors.affiliation: Department of Biological Science, The University of Tokushima Graduate School, 2-1 Minamijosanjima, Tokushima 770-8506, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Yuasa
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Masuda
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yoshikawa
authors.forename: Masami
authors.initials: M
authors.lastname: Nagahama
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Matsuda
authors.forename: Akihiko
authors.initials: A
authors.lastname: Tsuji
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D025461:Feedback, Physiological; D055785:Gene Knockdown Techniques; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000502:physiology*; D053507:Matrix Metalloproteinase 11 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D024510:Muscle Development / Q000235:genetics; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000502:physiology*; D018008:Myogenin / Q000235:genetics / Q000378:metabolism; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011498:Protein Precursors / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D017570:MyoD Protein; D018008:Myogenin; D018994:Myosin Light Chains; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011498:Protein Precursors; C042532:preproinsulin-like growth factor II; D007335:Insulin-Like Growth Factor II; D048051:p38 Mitogen-Activated Protein Kinases; C513086:Pcsk6 protein, mouse; D043484:Proprotein Convertases; D053507:Matrix Metalloproteinase 11