| First Author | Martin TD | Year | 2014 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 306 |
| Issue | 12 | Pages | E1397-405 |
| PubMed ID | 24801387 | Mgi Jnum | J:215265 |
| Mgi Id | MGI:5604972 | Doi | 10.1152/ajpendo.00064.2014 |
| Citation | Martin TD, et al. (2014) mTORC1 and JNK coordinate phosphorylation of the p70S6K1 autoinhibitory domain in skeletal muscle following functional overloading. Am J Physiol Endocrinol Metab 306(12):E1397-405 |
| abstractText | 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(3)(8)(9) and Thr(4)(2)(1)/Ser(4)(2)(4) sites on p70S6K1 was significantly elevated. Since the Thr(4)(2)(1)/Ser(4)(2)(4) 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(3)(8)(9) and Thr(4)(2)(1)/Ser(4)(2)(4) 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(4)(2)(1)/Ser(4)(2)(4) sites, it surprisingly enhanced phosphorylation of these sites during serum deprivation. JNK inhibition with SP600125 attenuated phosphorylation of the Thr(4)(2)(1)/Ser(4)(2)(4) sites, and in combination with TORIN2 both the effect of IGF-I and the enhanced Thr(4)(2)(1)/Ser(4)(2)(4) 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(4)(2)(1)/Ser(4)(2)(4) 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(4)(2)(1)/Ser(4)(2)(4) 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. |
