To maintain its activity, mTORC1 has to be located on the surface of the lysosome, where it is activated by binding to two classes of lysosome-localized small G proteins, i.e., Rheb and Rags. 2 Although it is clear that mTORC1 is also regulated by glucose availability at multiple levels, the underlying mechanisms have not been fully elucidated. 2, 3 This occurs independently of increases in AMP and ADP, the classical activators of AMPK. 1 It is already known that low glucose, and hence low levels of the glycolytic intermediate fructose-1,6-bisphosphate (FBP), can be sensed by aldolase to trigger AMPK activation via the lysosomal pathway. 1 In high glucose, mTORC1 is activated and shifts the metabolic program of the cell towards anabolic metabolism. ![]() 1 In low glucose, AMPK is activated and phosphorylates a wide range of downstream targets to maintain energy homeostasis, by switching on catabolic pathways while switching off ATP-consuming processes. As well as glucose being the major carbon nutrient for most cells, its availability also acts as a gate-keeper exerting a switch between anabolic and catabolic metabolism, with the protein kinases mTORC1 and AMP-activated protein kinase (AMPK) being the two master controllers.
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