Pyruvate kinase type M2 promotes tumour cell exosome release via phosphorylating synaptosome-associated protein 23

Yao Wei, Dong Wang, Fangfang Jin, Zhen Bian, Limin Li, Hongwei Liang, Mingzhen Li, Lei Shi, Chaoyun Pan, Dihan Zhu, Xi Chen, Gang Hu (), Yuan Liu (), Chen-Yu Zhang () and Ke Zen ()
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Yao Wei: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing Advanced Institute for Life Sciences, School of Life Sciences, Nanjing University
Dong Wang: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing Advanced Institute for Life Sciences, School of Life Sciences, Nanjing University
Fangfang Jin: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing Advanced Institute for Life Sciences, School of Life Sciences, Nanjing University
Zhen Bian: Center for Immunology, Georgia State University
Limin Li: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing Advanced Institute for Life Sciences, School of Life Sciences, Nanjing University
Hongwei Liang: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing Advanced Institute for Life Sciences, School of Life Sciences, Nanjing University
Mingzhen Li: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing Advanced Institute for Life Sciences, School of Life Sciences, Nanjing University
Lei Shi: Center for Immunology, Georgia State University
Chaoyun Pan: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing Advanced Institute for Life Sciences, School of Life Sciences, Nanjing University
Dihan Zhu: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing Advanced Institute for Life Sciences, School of Life Sciences, Nanjing University
Xi Chen: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing Advanced Institute for Life Sciences, School of Life Sciences, Nanjing University
Gang Hu: School of Medicine and Life Sciences, Nanjing University of Chinese Medicine
Yuan Liu: Center for Immunology, Georgia State University
Chen-Yu Zhang: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing Advanced Institute for Life Sciences, School of Life Sciences, Nanjing University
Ke Zen: State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing Advanced Institute for Life Sciences, School of Life Sciences, Nanjing University

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Tumour cells secrete exosomes that are involved in the remodelling of the tumour–stromal environment and promoting malignancy. The mechanisms governing tumour exosome release, however, remain incompletely understood. Here we show that tumour cell exosomes secretion is controlled by pyruvate kinase type M2 (PKM2), which is upregulated and phosphorylated in tumours. During exosome secretion, phosphorylated PKM2 serves as a protein kinase to phosphorylate synaptosome-associated protein 23 (SNAP-23), which in turn enables the formation of the SNARE complex to allow exosomes release. Direct phosphorylation assay and mass spectrometry confirm that PKM2 phosphorylates SNAP-23 at Ser95. Ectopic expression of non-phosphorylated SNAP-23 mutant (Ser95→Ala95) significantly reduces PKM2-mediated exosomes release whereas expression of selective phosphomimetic SNAP-23 mutants (Ser95→Glu95 but not Ser20→Glu20) rescues the impaired exosomes release induced by PKM2 knockdown. Our findings reveal a non-metabolic function of PKM2, an enzyme associated with tumour cell reliance on aerobic glycolysis, in promoting tumour cell exosome release.

Date: 2017
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DOI: 10.1038/ncomms14041

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