Signaling Discordance in S6K1 Regulation as a Consequence of mTOR Dysregulation by various Inhibitors

Abstract

Nutrient excess has overpowered the conservatory mechanisms letting newlinemetabolic diseases burgeon. Diabetes and disabilities associated with insulin newlineresistance have reached alarming proportions claiming more lives, health newlinebudget and economic drain. S6K1 has been attributed to be the major propagator of insulin resistance with knockdown models showing marked reduction in propensity for age-related and diet-related pathologies along with outstanding insulin sensitivity. Some of the major regulators of metabolic newlinecontrol like AMPK, GSK3beta are known to modulate S6K1 to fine tune signals for metabolic adjustments. Major drawback posed towards meaningful inhibition of this enzyme to ameliorate insulin resistance and age related infirmities is by the dysregulation of its upstream kinase and much reputed regulator mTORC1. Many potent and specific inhibitors of this kinase have newlinerevealed functions that preclude the mechanism followed by rapamycin which newlinehad long been touted as the reliable and specific inhibitory agent of mTORC1. newlineHypoglycemics like metformin, troglitazone and naturals compounds like caffeine have been observed to inhibit S6K1 and many other effectors of mTORC1 without considerable involvement of mTORC1 per se. This assumed even more importance for investigation in light of studies that have newlineimplicated mTOR independent influence of enzymes, AMPK, DRAK2 and GSK3beta on S6K1.In fact, much discordance can be discerned in the reported effect of these kinases on mTORC1 per se in the past with the individual influence they have on S6K1, presented lately. newlineWe provide evidence that AMPK actually stimulates S6K1 irrespective of its newlineeffect on mTORC1 and similar to DRAK2 acts on S6K1 in a manner that is mechanistically opposite to caffeine inhibition of this kinase. Further, caffeine, a natural hypoglycemic differs from metformin and even rapamycin in its mechanism of action and actually inhibits S6K1 through mTORC2. newlineAlso, GSK 3 beta stimulated Ser 394 is not pre-requisite for mTORC1 to newlinephosphorylate and activate S6K.....