Evaluation of mTORC1 Independent Signals with Potential to Regulate P70S6 Kinase

Abstract

S6K1, a member of AGC family of protein kinases, is an important signaling kinase newlinerequired for cell growth and proliferation. It responds to various growth factor signals newline(Insulin, PDGF, etc), nutrients (amino acids) and energy levels via its upstream newlineregulator mTOR that phosphorylates and activates S6K1 to propagate signals newlinedownstream. The regulation of S6K1 has been largely attributed to the dynamics of newlinethree phosphorylations at critical regions of turn motif, hydrophobic motif (HM) and newlineActivation/T loop of the enzyme. While the turn motif phosphorylation appears newlineconstitutive, the other two phosphorylations exclusively share the burden of S6K1 newlineregulation. The phosphorylation at hydrophobic motif has been attributed to the newlinekinase activity of mTOR; which in the form of a complex, mTORC1, is recruited by a newlinescaffold protein, Raptor on amino terminal TOS motif of S6K1. Phosphorylation at newlineHM acts as a precursor for the phosphorylation at the activation loop (AL), carried out newlineby another kinase, PDK1.These sequential phosphorylations have hence been newlineconsidered to be indispensible for the complete activation of S6K1. Accordingly newlineinactivation of mTORC1 by rapamycin resulting in loss of HM phosphorylation with newlineresultant loss of phosphorylation at the AL is the model put forward to explain newlineinhibition by rapamycin. The implication of mTORC1 to phosphorylate HM however, newlinelacks concrete evidence and is merely based on the ability of mTORC1 to bind newlinerapamycin. Further rapamycin sensitivity exhibited by S6K1 lacking HM newlinephosphorylation also invites questions. Furthermore, studies of late have shown the newlinepresence of HM phosphorylation in S6K1 variant truncated of its both the termini newline(S6K1and#916;NT/and#916;CT) isolated from rapamycin-treated cells. This has been attributed to newlinerapamycin insensitive kinase, mTORC2 that supposedly mediates the phosphorylation newlinein a non-physiological manner. These observations question the idea that mTORC1 newlinemay represent the sole S6K1 Thr412 kinase. Kinases like DRAK2, amongst others newlinehave also figured as candidate....