Ubiquitin Ligase Cbl-b Is a Negative Regulator for Insulin-Like Growth Factor 1 Signaling during Muscle Atrophy Caused by Unloading
| Autor: | Edward M. Mills, Jumpei Goto, Takeshi Nikawa, Kenneth M. Baldwin, Koji Yasutomo, Shin'ichi Takeda, Akira Higashibata, Kazumi Ishidoh, Keisuke Nagano, Reiko Nakao, Ikuya Nonaka, Ayako Ohno, Natsuo Yasui, Eiki Kominami, Keiji Tanaka, Chiharu Yamada, Katsuya Hirasaka, Yuushi Okumura |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Male
medicine.medical_specialty medicine.medical_treatment Molecular Sequence Data Muscle Proteins Protein degradation Cell Line Rats Sprague-Dawley Mice Insulin-like growth factor Atrophy Ubiquitin Internal medicine medicine Animals Humans Amino Acid Sequence Proto-Oncogene Proteins c-cbl Insulin-Like Growth Factor I Muscle Skeletal Molecular Biology Adaptor Proteins Signal Transducing Mice Knockout SKP Cullin F-Box Protein Ligases biology Growth factor Forkhead Box Protein O3 Forkhead Transcription Factors Articles Cell Biology Space Flight medicine.disease Muscle atrophy Rats Ubiquitin ligase Mice Inbred C57BL Muscular Atrophy Endocrinology Hindlimb Suspension Insulin Receptor Substrate Proteins biology.protein Phosphorylation medicine.symptom Oligopeptides Signal Transduction |
| Zdroj: | Molecular and Cellular Biology. 29:4798-4811 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.01347-08 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|