title: AMPK directly inhibits NDPK through a phosphoserine switch to maintain cellular homeostasis.
abstract: AMP-activated protein kinase (AMPK) is a key energy sensor that regulates metabolism to maintain cellular energy balance. AMPK activation has also been proposed to mimic benefits of caloric restriction and exercise. Therefore, identifying downstream AMPK targets could elucidate new mechanisms for maintaining cellular energy homeostasis. We identified the phosphotransferase nucleoside diphosphate kinase (NDPK), which maintains pools of nucleotides, as a direct AMPK target through the use of two-dimensional differential in-gel electrophoresis. Furthermore, we mapped the AMPK/NDPK phosphorylation site (serine 120) as a functionally potent enzymatic "off switch" both in vivo and in vitro. Because ATP is usually the most abundant cellular nucleotide, NDPK would normally consume ATP, whereas AMPK would inhibit NDPK to conserve energy. It is intriguing that serine 120 is mutated in advanced neuroblastoma, which suggests a mechanism by which NDPK in neuroblastoma can no longer be inhibited by AMPK-mediated phosphorylation. This novel placement of AMPK upstream and directly regulating NDPK activity has widespread implications for cellular energy/nucleotide balance, and we demonstrate in vivo that increased NDPK activity leads to susceptibility to energy deprivation-induced death.
authors: Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors: Rob U
authors: RU
authors: Onyenwoke
authors: Lawrence J
authors: LJ
authors: Forsberg
authors: Lucy
authors: L
authors: Liu
authors: Tyisha
authors: T
authors: Williams
authors: Oscar
authors: O
authors: Alzate
authors: Jay E
authors: JE
authors: Brenman
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000201:enzymology; D045744:Cell Line, Tumor; D004331:Drosophila melanogaster / Q000201:enzymology; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D009701:Nucleoside-Diphosphate Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D057825:Two-Dimensional Difference Gel Electrophoresis
chemical_list: D010768:Phosphoserine; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D009701:Nucleoside-Diphosphate Kinase