@article{4ad848a8f392407395c3dbde51ec1c8b,
title = "Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose Production",
abstract = "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.",
keywords = "cyclin-dependent kinase, enzyme regulation, hepatic glucose production, insulin resistance, metabolism, nuclear localization, phosphorylation, pyruvate kinase, sub-cellular localization",
author = "Gassaway, \{Brandon M.\} and Cardone, \{Rebecca L.\} and Padyana, \{Anil K.\} and Petersen, \{Max C.\} and Judd, \{Evan T.\} and Sebastian Hayes and Shuilong Tong and Barber, \{Karl W.\} and Maria Apostolidi and Abudukadier Abulizi and Sheetz, \{Joshua B.\} and Kshitiz and Aerni, \{Hans R.\} and Stefan Gross and Charles Kung and Samuel, \{Varman T.\} and Shulman, \{Gerald I.\} and Kibbey, \{Richard G.\} and Jesse Rinehart",
note = "Funding Information: This work was supported by National Institutes of Health (NIH) grants R01GM117230, P01DK017433, and P30DK45735 to J.R.; R01 DK110181 and R01 DK108283 to R.G.K.; and R01 DK-11674, R01 DK-11968, R01 DK-113984, and P30 DK-045735 to G.I.S. as well as generous funding from Agios Pharmaceuticals. B.M.G. and K.W.B. are supported by National Science Foundation Graduate Research Fellowship grant DGE1122492. M.C.P. is supported by NIH Medical Scientist Training Program grants T32GM007205 and F30DK104596. We thank Terence Wu of the West Campus Analytical Core and Vladimir Polejaev of the West Campus Imaging Core for training on the use and maintenance of equipment, James Lee at the Dana-Farber Cancer Institute Molecular Biology Core Facility (DFCI MBCF) for the intact MS analysis, the Yale Liver Center (supported by P30 DK034989) for hepatocyte isolation, and Amanda Kedaigle and Jennifer Wilson for their help in using Omicsintegrator. Conceptualization, B.M.G. R.G.K. and J.R.; Methodology, B.M.G. R.L.C. A.K.P. M.C.P. E.T.J. S.H. S.T. K.W.B. M.A. J.B.S. K. H.R.A. and S.G.; Investigation, B.M.G. R.L.C. A.K.P. M.C.P. E.T.J. S.H. S.T. K.W.B. J.B.S. M.A. A.A. and K.; Writing—Original Draft, B.M.G. and J.R.; Writing—Review and Editing, B.M.G. A.K.P. C.K. V.T.S. G.I.S. R.G.K. and J.R.; Funding Acquisition, B.M.G. G.I.S. R.G.K. and J.R.; Resources, C.K. G.I.S. R.G.K. and J.R.; Supervision, C.K. V.T.S. G.I.S. R.G.K. and J.R. The authors declare no competing interests. Funding Information: This work was supported by National Institutes of Health ( NIH ) grants R01GM117230 , P01DK017433 , and P30DK45735 to J.R.; R01 DK110181 and R01 DK108283 to R.G.K.; and R01 DK-11674 , R01 DK-11968 , R01 DK-113984 , and P30 DK-045735 to G.I.S., as well as generous funding from Agios Pharmaceuticals . B.M.G. and K.W.B. are supported by National Science Foundation Graduate Research Fellowship grant DGE1122492 . M.C.P. is supported by NIH Medical Scientist Training Program grants T32GM007205 and F30DK104596 . We thank Terence Wu of the West Campus Analytical Core and Vladimir Polejaev of the West Campus Imaging Core for training on the use and maintenance of equipment, James Lee at the Dana-Farber Cancer Institute Molecular Biology Core Facility (DFCI MBCF) for the intact MS analysis, the Yale Liver Center (supported by P30 DK034989 ) for hepatocyte isolation, and Amanda Kedaigle and Jennifer Wilson for their help in using Omicsintegrator. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = dec,
day = "10",
doi = "10.1016/j.celrep.2019.11.009",
language = "English",
volume = "29",
pages = "3394--3404.e9",
journal = "Cell Reports",
issn = "2211-1247",
number = "11",
}