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

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.

• Authors: Lei Lv, Yan-Ping Xu, Di Zhao, Fu-Long Li, Wei Wang, Naoya Sasaki, Ying Jiang, Xin Zhou, Ting-Ting Li, Kun-Liang Guan, Qun-Ying Lei, Yue Xiong
• Journal: Molecular cell (Mol Cell) Vol. 52 Issue 3 Pg. 340-52 (Nov 07 2013) ISSN: 1097-4164 [Electronic] United States
• PMID: 24120661 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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