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

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 acety...

Full description

Saved in:
Bibliographic Details
Published in:Molecular cell 2013-11, Vol.52 (3), p.340-352
Main Authors: Lv, Lei, Xu, Yan-Ping, Zhao, Di, Li, Fu-Long, Wang, Wei, Sasaki, Naoya, Jiang, Ying, Zhou, Xin, Li, Ting-Ting, Guan, Kun-Liang, Lei, Qun-Ying, Xiong, Yue
Format: Article
Language:English
Subjects:
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
p300-CBP Transcription Factors - metabolism
Thyroid Hormone-Binding Proteins
Thyroid Hormones - genetics
Thyroid Hormones - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2013.09.004