Nebulin and N-WASP Cooperate to Cause IGF-1-Induced Sarcomeric Actin Filament Formation

• Published in: Science (American Association for the Advancement of Science) 2010-12, Vol.330 (6010), p.1536-1540
• Main Authors: Takano, Kazunori, Watanabe-Takano, Haruko, Suetsugu, Shiro, Kurita, Souichi, Tsujita, Kazuya, Kimura, Sumiko, Karatsu, Takashi, Takenawa, Tadaomi, Endo, Takeshi
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - metabolism; Actins; Actins - metabolism; Analytical, structural and metabolic biochemistry; Animals; Bands; Biological and medical sciences; Cellular biology; Cercopithecus aethiops; COS Cells; Enlargement; Evolution; Filaments; Fundamental and applied biological sciences. Psychology; Genomes; Glycogens; Glycoproteins; Growth factors; Hypertrophy; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factors; Maturation; Mice; Mice, Inbred ICR; Microfilaments; Muscle Development; Muscle Proteins - chemistry; Muscle Proteins - metabolism; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscles; Musculoskeletal system; Myofibrils - metabolism; Nucleation; Pathogens; Phosphatidylinositol 3-Kinase - metabolism; Phosphorylation; Plants; Protein Binding; Protein Interaction Domains and Motifs; Protein synthesis; Proteins; Proto-Oncogene Proteins c-akt - metabolism; RNA Interference; Sarcomeres - metabolism; Signal Transduction; Skeletal muscle; src Homology Domains; Striated muscle. Tendons; Vertebrates: osteoarticular system, musculoskeletal system; Wiskott-Aldrich Syndrome Protein, Neuronal - chemistry; Wiskott-Aldrich Syndrome Protein, Neuronal - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1197767

Insulin-like growth factor 1 (IGF-1) induces skeletal muscle maturation and enlargement (hypertrophy). These responses require protein synthesis and myofibril formation (myofibrillogenesis). However, the signaling mechanisms of myofibrillogenesis remain obscure. We found that IGF-1-induced phosphatidylinositol 3-kinase-Akt signaling formed a complex of nebulin and N-WASP at the Z bands of myofibrils by interfering with glycogen synthase kinase-3β in mice. Although N-WASP is known to be an activator of the Arp2/3 complex to form branched actin filaments, the nebulin-N-WASP complex caused actin nucleation for unbranched actin filament formation from the Z bands without the Arp2/3 complex. Furthermore, N-WASP was required for IGF-1-induced muscle hypertrophy. These findings present the mechanisms of IGF-1-induced actin filament formation in myofibrillogenesis required for muscle maturation and hypertrophy and a mechanism of actin nucleation.