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

نویسندگان

  • Tony D Martin
  • Michael D Dennis
  • Bradley S Gordon
  • Scot R Kimball
  • Leonard S Jefferson
چکیده

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 Thr³⁸⁹ and Thr⁴²¹/Ser⁴²⁴ sites on p70S6K1 was significantly elevated. Since the Thr⁴²¹/Ser⁴²⁴ 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 Thr³⁸⁹ and Thr⁴²¹/Ser⁴²⁴ 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 Thr⁴²¹/Ser⁴²⁴ sites, it surprisingly enhanced phosphorylation of these sites during serum deprivation. JNK inhibition with SP600125 attenuated phosphorylation of the Thr⁴²¹/Ser⁴²⁴ sites, and in combination with TORIN2 both the effect of IGF-I and the enhanced Thr⁴²¹/Ser⁴²⁴ 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 Thr⁴²¹/Ser⁴²⁴ 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 Thr⁴²¹/Ser⁴²⁴ 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.

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عنوان ژورنال:
  • American journal of physiology. Endocrinology and metabolism

دوره 306 12  شماره 

صفحات  -

تاریخ انتشار 2014