Fyn phosphorylates AMPK to inhibit AMPK activity and AMP-dependent activation of autophagy

Eijiro Yamada, Shuichi Okada, Claire C. Bastie, Manu Vatish, Yasuyo Nakajima, Ryo Shibusawa, Atsushi Ozawa, Jeffrey E. Pessin, Masanobu Yamada

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

We previously demonstrated that proto-oncogene Fyn decreased energy expenditure and increased metabolic phenotypes. Also Fyn decreased autophagymediated muscle mass by directly inhibiting LKB1 and stimulating STAT3 activities, respectively. AMPK, a downstream target of LKB1, was recently identified as a key molecule controlling autophagy. Here we identified that Fyn phosphorylates the a subunit of AMPK on Y436 and inhibits AMPK enzymatic activity without altering the assembly state of the AMPK heterotrimeric complex. As pro-inflammatory mediators are reported modulators of the autophagy processes, treatment with the proinflammatory cytokine TNFα resulted in 1) increased Fyn activity 2) stimulated Fyndependent AMPKa tyrosine phosphorylation and 3) decreased AICAR-dependent AMPK activation. Importantly, TNFα induced inhibition of autophagy was not observed when AMPKa was mutated on Y436. 4) These data demonstrate that Fyn plays an important role in relaying the effects of TNFα on autophagy and apoptosis via phosphorylation and inhibition of AMPK.

Original languageEnglish (US)
Pages (from-to)74612-74629
Number of pages18
JournalOncotarget
Volume7
Issue number46
DOIs
StatePublished - Jan 1 2016

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Keywords

  • AMPK
  • Autophagy
  • Fyn
  • TNFα

ASJC Scopus subject areas

  • Oncology

Cite this

Yamada, E., Okada, S., Bastie, C. C., Vatish, M., Nakajima, Y., Shibusawa, R., Ozawa, A., Pessin, J. E., & Yamada, M. (2016). Fyn phosphorylates AMPK to inhibit AMPK activity and AMP-dependent activation of autophagy. Oncotarget, 7(46), 74612-74629. https://doi.org/10.18632/oncotarget.11916