The AMP-activated protein kinase pathway--new players upstream and downstream.
The AMP-activated protein kinase (AMPK) cascade is a sensor of cellular energy status. Whenever the cellular ATP:ADP ratio falls, owing to a stress that inhibits ATP production or increases ATP consumption, this is amplified by adenylate kinase into a much larger increase in the AMP:ATP ratio. AMP activates the system by binding to two tandem domains on the gamma subunits of AMPK, and this is antagonized by high concentrations of ATP. AMP binding causes activation by a sensitive mechanism involving phosphorylation of AMPK by the tumour suppressor LKB1. Once activated, AMPK switches on catabolic pathways that generate ATP while switching off ATP-consuming processes. As well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level, in particular by mediating the effects of hormones and cytokines such as leptin, adiponectin and ghrelin. A particularly interesting downstream target recently identified is TSC2 (tuberin). The LKB1-->AMPK-->TSC2 pathway negatively regulates the target of rapamycin (TOR), and this appears to be responsible for limiting protein synthesis and cell growth, and protecting against apoptosis, during cellular stresses such as glucose starvation.
Hardie
D Grahame
DG
Division of Molecular Physiology, Wellcome Trust Biocentre, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK. d.g.hardie@dundee.ac.uk
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000249:Adenosine Monophosphate / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival / Q000502:physiology; D025461:Feedback, Physiological / Q000502:physiology; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000502:physiology
D009097:Multienzyme Complexes; D012097:Repressor Proteins; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases