P70S6 kinase

p70S6 kinase or p70S6K is a serine/threonine kinase that acts downstream of PIP3 and phosphoinositide-dependent kinase-1 in the PI3 kinase pathway.^[1] As the name suggests, its target substrate is the S6 ribosomal protein.^[2] Phosphorylation of S6 induces protein synthesis at the ribosome.

The phosphorylation of P70S6K at threonine 389 has been used as a hallmark of activation by mTOR and correlated with autophagy inhibition in various situations. However, several recent studies suggest that the activity of P70S6K plays a more positive role in the increase of autophagy.^[3][4]

mTOR

P70S6 kinase is in a signaling pathway that includes mTOR (the mammalian target of rapamycin). mTOR can be activated in distinct ways, thereby activating p70S6K. For example, branched chain amino acids such as leucine are sufficient to activate mTOR, resulting in an increase in p70S6K phosphorylation (and thereby activating it). mTOR is also in a pathway downstream of the kinase Akt. Akt is typically activated upon stimulation of a cell with a growth factor (such as IGF-1). Akt then activates mTOR (by inhibiting the Tsc complex), leading to p70S6K activation.

Physical exercise activates protein synthesis via phosphorylation (activation) of p70S6K in a pathway that is dependent on mTOR. This has been demonstrated by using an inhibitor of mTOR, rapamycin, to block an increase in muscle mass, despite increases in load (e.g., exercise). Exercise has been shown to increase levels of IGF-1 in muscle, thus inducing the IGF-1/PI3K/Akt/P70S6K signaling pathway, and thereby increasing the protein synthesis required to build muscle.

References

1. Chung J, Grammer TC, Lemon KP, Kazlauskas A, Blenis J. (1994). "PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase". Nature 370 (6484): 71–75. doi:10.1038/370071a0. PMID 8015612.
2. Chung J, Kuo CJ, Crabtree GR, Blenis J. (1992). "Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases.". Cell 69 (7): 1227–1236. doi:10.1016/0092-8674(92)90643-Q. PMID 1377606.
3. Datan E, Shirazian A, Benjamin S, Matassov D, Tinari A, Malorni W, Lockshin RA, Garcia-Sastre A, Zakeri Z (2014). "mTOR/p70s6k signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza infection". Virology. 452-453 (march 2014): 175–190. doi:10.1016/j.virol.2014.01.008. PMC 4005847. PMID 24606695.
4. Ci Y, Shi K, An J, Yang Y, Hui K, Wu P, Shi L, Xu C (2014). "ROS inhibit autophagy by downregulating ULK1 mediated by the phosphorylation of p53 in selenite-treated NB4 cells". cell death and disease 5 (november 2014): 1–10. doi:10.1038/cddis.2014.506.