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Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear

Lei Lv1, Yan-Ping Xu, Di Zhao

  • 1Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai 200032, People's Republic of China; Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, People's Republic of China; School of Life Sciences, Fudan University 200032, People's Republic of China.

Molecular Cell
|October 15, 2013
PubMed

Insights

Pyruvate kinase M2 (PKM2) acetylation at K433 by p300 prevents its activation, promoting nuclear localization and protein kinase activity. This acetylation links cancer cell proliferation and transformation to PKM2

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • Alternative splicing of the pyruvate kinase M2 (PKM2) gene yields M1 and M2 isoforms, with M2 reexpressed in human cancers exhibiting nonmetabolic nuclear functions.
  • PKM2 functions as a protein kinase in the nucleus, playing a role in cellular processes beyond metabolism.

Purpose of the Study:

  • To investigate the regulatory mechanisms of PKM2, specifically focusing on post-translational modifications.
  • To determine the functional consequences of PKM2 acetylation at K433 on its activity and cellular localization.

Main Methods:

  • Identification of K433 as a site of acetylation by p300 acetyltransferase.
  • Analysis of the interaction between acetylated PKM2, fructose 1,6-bisphosphate (FBP), and its allosteric activation.
  • Assessment of the impact of acetylation-mimetic mutants on cell proliferation and tumorigenesis.
  • Correlation of K433 acetylation levels with cancer enrichment and cellular conditions.

Main Results:

  • PKM2 is acetylated by p300 at K433, a site unique to PKM2 that interacts with the allosteric activator FBP.
  • Acetylation at K433 inhibits PKM2 activation by preventing FBP binding, leading to increased nuclear accumulation and protein kinase activity.
  • An acetylation-mimetic PKM2(K433) mutant enhances cell proliferation and tumorigenesis.
  • K433 acetylation is modulated by cellular conditions (serum starvation, cell-cell contact, cell cycle stimulation, EGF, oncoprotein E7) and is enriched in breast cancers.

Conclusions:

  • K433 acetylation serves as a critical regulatory switch for PKM2, modulating its function from a cytoplasmic metabolic kinase to a nuclear protein kinase.
  • This acetylation links cellular proliferation and transformation processes to the altered activity and localization of PKM2 in cancer.

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