mTORC1 and JNK coordinate phosphorylation of the p70S6K1 autoinhibitory domain in skeletal muscle following functional overloading

作者：Martin Tony D; Dennis Michael D; Gordon Bradley S; Kimball Scot R^*; Jefferson Leonard S

来源：American Journal of Physiology - Endocrinology And Metabolism, 2014, 306(12): E1397-E1405.

DOI：10.1152/ajpendo.00064.2014

• MAPK signaling
• muscle hypertrophy
• tenotomy

The present project was designed to investigate phosphorylation of p70S6K1 in an animal model of skeletal muscle overload. Within 24 h of male Sprague-Dawley rats undergoing unilateral tenotomy to induce functional overloading of the plantaris muscle, phosphorylation of the Thr(389) and Thr(421)/Ser(424) sites on p70S6K1 was significantly elevated. Since the Thr(421)/Ser(424) sites are purportedly mammalian target of rapamycin complex 1 (mTORC1) independent, we sought to identify the kinase(s) responsible for their phosphorylation. Initially, we used IGF-I treatment of serum-deprived HEK-293E cells as an in vitro model system, because IGF-I promotes phosphorylation of p70S6K1 on both the Thr(389) and Thr(421)/Ser(424) sites in skeletal muscle and in cells in culture. We found that, whereas the mTOR inhibitor TORIN2 prevented the IGF-I-induced phosphorylation of the Thr(421)/Ser(424) sites, it surprisingly enhanced phosphorylation of these sites during serum deprivation. JNK inhibition with SP600125 attenuated phosphorylation of the Thr(421)/Ser(424) sites, and in combination with TORIN2 both the effect of IGF-I and the enhanced Thr(421)/Ser(424) phosphorylation during serum deprivation were ablated. In contrast, both JNK activation with anisomycin and knockdown of the mTORC2 subunit rictor specifically stimulated phosphorylation of the Thr(421)/Ser(424) sites, suggesting that mTORC2 represses JNK-mediated phosphorylation of these sites. The role of JNK in mediating p70S6K1 phosphorylation was confirmed in the animal model noted above, where rats treated with SP600125 exhibited attenuated Thr(421)/Ser(424) phosphorylation. Overall, the results provide evidence that the mTORC1 and JNK signaling pathways coordinate the site-specific phosphorylation of p70S6K1. They also identify a novel role for mTORC1 and mTORC2 in the inhibition of JNK.

• 出版日期2014-6-15