title: Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB2) isoenzyme by amino acids.
abstract: Reciprocal regulation of metabolism and signaling allows cells to modulate their activity in accordance with their metabolic resources. Thus, amino acids could activate signal transduction pathways that control cell metabolism. To test this hypothesis, we analyzed the effect of amino acids on fructose-2,6-bisphosphate (Fru-2,6-P2) metabolism. We demonstrate that amino acids increase Fru-2,6-P2 concentration in HeLa and in MCF7 human cells. In conjunction with this, 6-phosphofructo-2-kinase activity, glucose uptake, and lactate concentration were increased. These data correlate with the specific phosphorylation of heart 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB2) isoenzyme at Ser-483. This activation was mediated by the PI3K and p38 signaling pathways. Furthermore, Akt inactivation blocked PFKFB2 phosphorylation and Fru-2,6-P2 production, thereby suggesting that the above signaling pathways converge at Akt kinase. In accordance with these results, kinase assays showed that amino acid-activated Akt phosphorylated PFKFB2 at Ser-483 and that knockdown experiments confirmed that the increase in Fru-2,6-P2 concentration induced by amino acids was due to PFKFB2. In addition, similar effects on Fru-2,6-P2 metabolism were observed in freshly isolated rat cardiomyocytes treated with amino acids, which indicates that these effects are not restricted to human cancer cells. In these cardiomyocytes, the glucose consumption and the production of lactate and ATP suggest an increase of glycolytic flux. Taken together, these results demonstrate that amino acids stimulate Fru-2,6-P2 synthesis by Akt-dependent PFKFB2 phosphorylation and activation and show how signaling and metabolism are inextricably linked.
authors: Departament de Ciències Fisiològiques II, Campus de Bellvitge, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona 08907, Spain.
authors: Laura
authors: L
authors: Novellasdemunt
authors: Irantzu
authors: I
authors: Tato
authors: Aurea
authors: A
authors: Navarro-Sabate
authors: Marisol
authors: M
authors: Ruiz-Meana
authors: Andrés
authors: A
authors: Méndez-Lucas
authors: Jose Carlos
authors: JC
authors: Perales
authors: David
authors: D
authors: Garcia-Dorado
authors: Francesc
authors: F
authors: Ventura
authors: Ramon
authors: R
authors: Bartrons
authors: Jose Luis
authors: JL
authors: Rosa
mesh_terms: D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D005635:Fructosediphosphates / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology*; D025481:Phosphofructokinase-2 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000596:Amino Acids; D005635:Fructosediphosphates; D019344:Lactic Acid; D012694:Serine; D000255:Adenosine Triphosphate; C555744:PFKFB2 protein, human; D025481:Phosphofructokinase-2; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; C029063:fructose-1,6-diphosphate