title: Ubiquitin ligase Cbl-b is a negative regulator for insulin-like growth factor 1 signaling during muscle atrophy caused by unloading.
abstract: Skeletal muscle atrophy caused by unloading is characterized by both decreased responsiveness to myogenic growth factors (e.g., insulin-like growth factor 1 [IGF-1] and insulin) and increased proteolysis. Here, we show that unloading stress resulted in skeletal muscle atrophy through the induction and activation of the ubiquitin ligase Cbl-b. Upon induction, Cbl-b interacted with and degraded the IGF-1 signaling intermediate IRS-1. In turn, the loss of IRS-1 activated the FOXO3-dependent induction of atrogin-1/MAFbx, a dominant mediator of proteolysis in atrophic muscle. Cbl-b-deficient mice were resistant to unloading-induced atrophy and the loss of muscle function. Furthermore, a pentapeptide mimetic of tyrosine(608)-phosphorylated IRS-1 inhibited Cbl-b-mediated IRS-1 ubiquitination and strongly decreased the Cbl-b-mediated induction of atrogin-1/MAFbx. Our results indicate that the Cbl-b-dependent destruction of IRS-1 is a critical dual mediator of both increased protein degradation and reduced protein synthesis observed in unloading-induced muscle atrophy. The inhibition of Cbl-b-mediated ubiquitination may be a new therapeutic strategy for unloading-mediated muscle atrophy.
authors: Department of Nutritional Physiology, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto-cho, Tokushima, Japan.
authors: Reiko
authors: R
authors: Nakao
authors: Katsuya
authors: K
authors: Hirasaka
authors: Jumpei
authors: J
authors: Goto
authors: Kazumi
authors: K
authors: Ishidoh
authors: Chiharu
authors: C
authors: Yamada
authors: Ayako
authors: A
authors: Ohno
authors: Yuushi
authors: Y
authors: Okumura
authors: Ikuya
authors: I
authors: Nonaka
authors: Koji
authors: K
authors: Yasutomo
authors: Kenneth M
authors: KM
authors: Baldwin
authors: Eiki
authors: E
authors: Kominami
authors: Akira
authors: A
authors: Higashibata
authors: Keisuke
authors: K
authors: Nagano
authors: Keiji
authors: K
authors: Tanaka
authors: Natsuo
authors: N
authors: Yasui
authors: Edward M
authors: EM
authors: Mills
authors: Shin'ichi
authors: S
authors: Takeda
authors: Takeshi
authors: T
authors: Nikawa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D019417:Hindlimb Suspension; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013026:Space Flight; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; C492213:Cblb protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D009124:Muscle Proteins; D009842:Oligopeptides; D025801:Ubiquitin; D007334:Insulin-Like Growth Factor I; C486691:Fbxo32 protein, mouse; D050721:Proto-Oncogene Proteins c-cbl; D044843:SKP Cullin F-Box Protein Ligases