The SCF-Fbxo40 complex induces IRS1 ubiquitination in skeletal muscle, limiting IGF1 signaling.
Insulin-like growth factor 1 (IGF1) induces skeletal muscle hypertrophy by activating the IGF1R/IRS1/PI3K/Akt pathway. However the effect of IGF1 in differentiated muscle is limited by IRS1 ubiquitination and proteasome-mediated breakdown. In skeletal muscle, IGF1R activation sensitizes IRS1 to degradation, and a screen for the responsible E3 ligase identified Fbxo40 as mediating this rapid turnover of IRS1, since IRS1 loss can be rescued by knockdown of Fbxo40. In biochemical assays, an SCF E3 ligase complex containing Fbxo40 directly ubiquitinates IRS1, and this activity is enhanced by increased tyrosine phosphorylation of IRS1. Fbxo40 is muscle specific in expression and is upregulated during differentiation. Knockdown of Fbxo40 induces dramatic hypertrophy of myofibers. Mice null for Fbxo40 have increased levels of IRS1 and demonstrate enhanced body and muscle size during the growth phase associated with elevated IGF1 levels. These findings establish an important means of restraining IGF1's effects on skeletal muscle.
Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
Jun
J
Shi
Liqing
L
Luo
John
J
Eash
Chikwendu
C
Ibebunjo
David J
DJ
Glass
D000818:Animals; D002460:Cell Line; D044783:F-Box Proteins / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D014452:Ubiquitins / Q000378:metabolism
D044783:F-Box Proteins; C525753:FBXO40 protein, mouse; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D014452:Ubiquitins; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D044767:Ubiquitin-Protein Ligases