Ubiquitin Ligase Cbl-b is a Negative Regulator for Insulin-like Growth Factor 1 Signaling During Muscle Atrophy Caused by Unloading

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2009 Jun 24

PMID 19546233

Citations 87

Authors

Reiko Nakao

Katsuya Hirasaka

Jumpei Goto

Kazumi Ishidoh

Chiharu Yamada

Ayako Ohno

Yuushi Okumura

Ikuya Nonaka

Koji Yasutomo

Kenneth M Baldwin

Eiki Kominami

Akira Higashibata

Keisuke Nagano

Keiji Tanaka

Natsuo Yasui

Edward M Mills

Shinichi Takeda

Takeshi Nikawa

Affiliations

Soon will be listed here.

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.

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