The E3 ubiquitin ligase Fbxo40 targets IRS1 for degradation upon IGF1 treatment in skeletal myotubes, controlling muscle cell size
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Shi, Jun and Glass, David (2011) The E3 ubiquitin ligase Fbxo40 targets IRS1 for degradation upon IGF1 treatment in skeletal myotubes, controlling muscle cell size. Developemental Cell, 21 (5). pp. 835-847. ISSN 1534-5807
Abstract
Insulin-like growth factor 1 (IGF1) induces skeletal muscle hypertrophy by activating the IGF1R/IRS1/PI3K/Akt pathway. However, IRS1 is rapidly targeted and degraded by the proteasome soon after IGF1 stimulation, leading to a downregulation of this pathway. None of the previously discovered E3 ligases for IRS1 mediate this effect in muscle cells. Instead, the E3 ligase Fbxo40 is responsible for the targeting of IRS1 in skeletal myotubes upon IGF1 stimulation, as demonstrated by rescue of IRS1 upon knockdown of Fbxo40, and by the finding that Fbxo40 can directly ubiquitinate IRS1. Fbxo40 is muscle-specific in expression, and it is significantly upregulated upon differentiation from myoblasts to myotubes. In vivo, knockdown of Fbxo40 induces dramatic hypertrophy of skeletal myotubes. These findings establish an important, previously undiscovered, upstream checkpoint regulating IGF1 skeletal muscle hypertrophy.
| Item Type: | Article |
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| Additional Information: | author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used |
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| Date Deposited: | 13 Oct 2015 13:16 |
| Last Modified: | 13 Oct 2015 13:16 |
| URI: | https://oak.novartis.com/id/eprint/3002 |