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

Mol Cell. 2013 Nov 7;52(3):340-52. doi: 10.1016/j.molcel.2013.09.004. Epub 2013 Oct 10.

Abstract

Alternative splicing of the PKM2 gene produces two isoforms, M1 and M2, which are preferentially expressed in adult and embryonic tissues, respectively. The M2 isoform is reexpressed in human cancer and has nonmetabolic functions in the nucleus as a protein kinase. Here, we report that PKM2 is acetylated by p300 acetyltransferase at K433, which is unique to PKM2 and directly contacts its allosteric activator, fructose 1,6-bisphosphate (FBP). Acetylation prevents PKM2 activation by interfering with FBP binding and promotes the nuclear accumulation and protein kinase activity of PKM2. Acetylation-mimetic PKM2(K433) mutant promotes cell proliferation and tumorigenesis. K433 acetylation is decreased by serum starvation and cell-cell contact, increased by cell cycle stimulation, epidermal growth factor (EGF), and oncoprotein E7, and enriched in breast cancers. Hence, K433 acetylation links cell proliferation and transformation to the switch of PKM2 from a cytoplasmic metabolite kinase to a nuclear protein kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation*
  • Alternative Splicing / genetics
  • Carcinogenesis / genetics*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Proliferation
  • Fructosediphosphates / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Lysine / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Thyroid Hormones / genetics
  • Thyroid Hormones / metabolism*
  • p300-CBP Transcription Factors / metabolism

Substances

  • Carrier Proteins
  • Fructosediphosphates
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Thyroid Hormones
  • thyroid hormone-binding proteins
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Lysine
  • fructose-1,6-diphosphate