title: Reciprocal regulation of AMP-activated protein kinase and phospholipase D.
abstract: AMP-activated protein kinase (AMPK), a critical sensor of energy sufficiency, acts as central metabolic switch in cell metabolism. Once activated by low energy status, AMPK phosphorylates key regulatory substrates and turns off anabolic biosynthetic pathways. In contrast, the mammalian/mechanistic target of rapamycin (mTOR) is active when there are sufficient nutrients for anabolic reactions. A critical factor regulating mTOR is phosphatidic acid (PA), a central metabolite of membrane lipid biosynthesis and the product of the phospholipase D (PLD)-catalyzed hydrolysis of phosphatidylcholine. PLD is a downstream target of the GTPase Rheb, which is turned off in response to AMPK via the tuberous sclerosis complex. Although many studies have linked AMPK with mTOR, very little is known about the connection between AMPK and PLD. In this report, we provide evidence for reciprocal regulation of PLD by AMPK and regulation of AMPK by PLD and PA. Suppression of AMPK activity led to an increase in PLD activity, and conversely, activation of AMPK suppressed PLD activity. Suppression of PLD activity resulted in elevated AMPK activity. Exogenously supplied PA abolished the inhibitory effects of elevated AMPK activity on mTOR signaling. In contrast, exogenously supplied PA could not overcome the effect AMPK activation if either mTOR or Raptor was suppressed, indicating that the inhibitory effects of PLD and PA on AMPK activity are mediated by mTOR. These data suggest a reciprocal feedback mechanism involving AMPK and the PLD/mTOR signaling node in cancer cells with therapeutic implications.
authors: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065.
authors: Suman
authors: S
authors: Mukhopadhyay
authors: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065.
authors: Mahesh
authors: M
authors: Saqcena
authors: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065.
authors: Amrita
authors: A
authors: Chatterjee
authors: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065.
authors: Avalon
authors: A
authors: Garcia
authors: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065.
authors: Maria A
authors: MA
authors: Frias
authors: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065 foster@genectr.hunter.cuny.edu.
authors: David A
authors: DA
authors: Foster
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology* / Q000378:metabolism; D010712:Phosphatidic Acids / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D010712:Phosphatidic Acids; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D010739:Phospholipase D
keywords: AMP-activated Protein Kinase (AMPK); Mammalian Target of Rapamycin (mTOR); Phosphatidic Acid; Phospholipase D (PLD); Tuberous Sclerosis Complex (TSC)
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