Inhibition of AMP Kinase by the Protein Phosphatase 2A Heterotrimer, PP2APpp2r2d.

Biny K Joseph, Hsing-Yin Liu, Jamie Francisco, Devanshi Pandya, Melissa Donigan, Christina Gallo-Ebert, Caroline Giordano, Adam Bata, Joseph T Nickels

The Journal of biological chemistry 2015 Apr 24

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AMP kinase is a heterotrimeric serine/threonine protein kinase that regulates a number of metabolic processes, including lipid biosynthesis and metabolism. AMP kinase activity is regulated by phosphorylation, and the kinases involved have been uncovered. The particular phosphatases counteracting these kinases remain elusive. Here we discovered that the protein phosphatase 2A heterotrimer, PP2A(Ppp2r2d), regulates the phosphorylation state of AMP kinase by dephosphorylating Thr-172, a residue that activates kinase activity when phosphorylated. Co-immunoprecipitation and co-localization studies indicated that PP2A(Ppp2r2d) directly interacted with AMP kinase. PP2A(Ppp2r2d) dephosphorylated Thr-172 in rat aortic and human vascular smooth muscle cells. A positive correlation existed between decreased phosphorylation, decreased acetyl-CoA carboxylase Acc1 phosphorylation, and sterol response element-binding protein 1c-dependent gene expression. PP2A(Ppp2r2d) protein expression was up-regulated in the aortas of mice fed a high fat diet, and the increased expression correlated with increased blood lipid levels. Finally, we found that the aortas of mice fed a high fat diet had decreased AMP kinase Thr-172 phosphorylation, and contained an Ampk-PP2A(Ppp2r2d) complex. Thus, PP2A(Ppp2r2d) may antagonize the aortic AMP kinase activity necessary for maintaining normal aortic lipid metabolism. Inhibiting PP2A(Ppp2r2d) or activating AMP kinase represents a potential pharmacological treatment for many lipid-related diseases. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Citation

Biny K Joseph, Hsing-Yin Liu, Jamie Francisco, Devanshi Pandya, Melissa Donigan, Christina Gallo-Ebert, Caroline Giordano, Adam Bata, Joseph T Nickels. Inhibition of AMP Kinase by the Protein Phosphatase 2A Heterotrimer, PP2APpp2r2d. The Journal of biological chemistry. 2015 Apr 24;290(17):10588-98