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  • Title: mTORC1 and JNK coordinate phosphorylation of the p70S6K1 autoinhibitory domain in skeletal muscle following functional overloading.
    Author: Martin TD, Dennis MD, Gordon BS, Kimball SR, Jefferson LS.
    Journal: Am J Physiol Endocrinol Metab; 2014 Jun 15; 306(12):E1397-405. PubMed ID: 24801387.
    Abstract:
    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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