Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose Production
Brandon M. Gassaway,
Rebecca L. Cardone,
Anil K. Padyana,
Max C. Petersen,
Evan T. Judd,
Sebastian Hayes,
Shuilong Tong,
Karl W. Barber,
Maria Apostolidi,
Abudukadier Abulizi,
Joshua B. Sheetz,
Kshitiz,
Hans R. Aerni,
Stefan Gross,
Charles Kung,
Varman T. Samuel,
Gerald I. Shulman,
Richard G. Kibbey,
Jesse Rinehart
Affiliations
Brandon M. Gassaway
Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA; Department of Systems Biology Institute, Yale University, New Haven, CT, USA
Rebecca L. Cardone
Department of Internal Medicine, Yale University, New Haven, CT, USA
Anil K. Padyana
Agios Pharmaceuticals, Cambridge, MA, USA
Max C. Petersen
Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA; Department of Internal Medicine, Yale University, New Haven, CT, USA
Evan T. Judd
Agios Pharmaceuticals, Cambridge, MA, USA
Sebastian Hayes
Agios Pharmaceuticals, Cambridge, MA, USA
Shuilong Tong
Viva Biotech, Shanghai, China
Karl W. Barber
Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA; Department of Systems Biology Institute, Yale University, New Haven, CT, USA
Maria Apostolidi
Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA; Department of Systems Biology Institute, Yale University, New Haven, CT, USA
Abudukadier Abulizi
Department of Internal Medicine, Yale University, New Haven, CT, USA
Joshua B. Sheetz
Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA
Kshitiz
Department of Systems Biology Institute, Yale University, New Haven, CT, USA; Department of Biomedical Engineering, Yale University, New Haven, CT, USA
Hans R. Aerni
Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA; Department of Systems Biology Institute, Yale University, New Haven, CT, USA
Stefan Gross
Agios Pharmaceuticals, Cambridge, MA, USA
Charles Kung
Agios Pharmaceuticals, Cambridge, MA, USA
Varman T. Samuel
Department of Internal Medicine, Yale University, New Haven, CT, USA; Veterans Affairs Medical Center, West Haven, CT, USA
Gerald I. Shulman
Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA; Department of Internal Medicine, Yale University, New Haven, CT, USA
Richard G. Kibbey
Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA; Department of Internal Medicine, Yale University, New Haven, CT, USA
Jesse Rinehart
Department of Cellular and Molecular Physiology, Yale University, New Haven, CT, USA; Department of Systems Biology Institute, Yale University, New Haven, CT, USA; Corresponding author
Summary: Pyruvate kinase is an important enzyme in glycolysis and a key metabolic control point. We recently observed a pyruvate kinase liver isoform (PKL) phosphorylation site at S113 that correlates with insulin resistance in rats on a 3 day high-fat diet (HFD) and suggests additional control points for PKL activity. However, in contrast to the classical model of PKL regulation, neither authentically phosphorylated PKL at S12 nor S113 alone is sufficient to alter enzyme kinetics or structure. Instead, we show that cyclin-dependent kinases (CDKs) are activated by the HFD and responsible for PKL phosphorylation at position S113 in addition to other targets. These CDKs control PKL nuclear retention, alter cytosolic PKL activity, and ultimately influence glucose production. These results change our view of PKL regulation and highlight a previously unrecognized pathway of hepatic CDK activity and metabolic control points that may be important in insulin resistance and type 2 diabetes. : Gassaway et al. identify a diet-induced, cyclin-dependent kinase-regulated phosphorylation site at S113 on pyruvate kinase. Although they determine that neither phosphorylation of this site nor the canonical PKA-regulated S12 site directly impacts enzyme kinetics, they demonstrate that S113 phosphorylation alters pyruvate kinase subcellular localization and influences glucose production. Keywords: pyruvate kinase, cyclin-dependent kinase, metabolism, phosphorylation, hepatic glucose production, enzyme regulation, insulin resistance, sub-cellular localization, nuclear localization
