Protein phosphatase 4 dephosphorylates phosphofructokinase-1 to regulate its enzymatic activity
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Most cancer cells utilize glucose at a high rate to produce energyand precursors for the biosynthesis of macromolecules such aslipids, proteins, and nucleic acids. This phenomenon is calledthe Warburg effect or aerobic glycolysis— this distinct characteristicis an attractive target for developing anticancer drugs. Here, we found that Phosphofructokinase-1 (PFK-1) is a substrateof the Protein Phosphatase 4 catalytic subunit (PP4C)/PP4 regulatorysubunit 1 (PP4R1) complex by using immunoprecipitationand in vitro assay. While manipulation of PP4C/PP4R1does not have a critical impact on PFK-1 expression, the absenceof the PP4C/PP4R1 complex increases PFK-1 activity. AlthoughPP4C depletion or overexpression does not cause adramatic change in the overall glycolytic rate, PP4R1 depletioninduces a considerable increase in both basal and compensatoryglycolytic rates, as well as the oxygen consumption rate, indicatingoxidative phosphorylation. Collectively, the PP4C/PP4R1complex regulates PFK-1 activity by reversing its phosphorylationand is a promising candidate for treating glycolytic disordersand cancers. Targeting PP4R1 could be a more efficientand safer strategy to avoid pleiotropic effects than targeting PP4Cdirectly.
Abstract
Most cancer cells utilize glucose at a high rate to produce energyand precursors for the biosynthesis of macromolecules such aslipids, proteins, and nucleic acids. This phenomenon is calledthe Warburg effect or aerobic glycolysis— this distinct characteristicis an attractive target for developing anticancer drugs. Here, we found that Phosphofructokinase-1 (PFK-1) is a substrateof the Protein Phosphatase 4 catalytic subunit (PP4C)/PP4 regulatorysubunit 1 (PP4R1) complex by using immunoprecipitationand in vitro assay. While manipulation of PP4C/PP4R1does not have a critical impact on PFK-1 expression, the absenceof the PP4C/PP4R1 complex increases PFK-1 activity. AlthoughPP4C depletion or overexpression does not cause adramatic change in the overall glycolytic rate, PP4R1 depletioninduces a considerable increase in both basal and compensatoryglycolytic rates, as well as the oxygen consumption rate, indicatingoxidative phosphorylation. Collectively, the PP4C/PP4R1complex regulates PFK-1 activity by reversing its phosphorylationand is a promising candidate for treating glycolytic disordersand cancers. Targeting PP4R1 could be a more efficientand safer strategy to avoid pleiotropic effects than targeting PP4Cdirectly.
참고문헌 (41)
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