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

  • Nat Commun. 2017 Jan 9:8:14041. doi: 10.1038/ncomms14041.
Yao Wei  1  2 ,  Dong Wang  1 ,  Fangfang Jin  1 ,  Zhen Bian  3 ,  Limin Li  1 ,  Hongwei Liang  1 ,  Mingzhen Li  1 ,  Lei Shi  3 ,  Chaoyun Pan  1 ,  Dihan Zhu  1 ,  Xi Chen  1 ,  Gang Hu  2 ,  Yuan Liu  3 ,  Chen-Yu Zhang  1 ,  Ke Zen  1  3
Affiliations
  • 1. 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, Nanjing, Jiangsu 210093, China.
  • 2. School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
  • 3. Center for Immunology, Inflammation and Infectious Diseases &Department of Biology, Georgia State University, Atlanta, Georgia 30302, USA.
PMID: 28067230 DOI: 10.1038/ncomms14041
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.