Oncotarget

Research Papers: Autophagy and Cell Death:

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 and Masanobu Yamada

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Oncotarget. 2016; 7:74612-74629. https://doi.org/10.18632/oncotarget.11916

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Abstract

Eijiro Yamada1, Shuichi Okada1, Claire C. Bastie2, Manu Vatish4, Yasuyo Nakajima1, Ryo Shibusawa1, Atsushi Ozawa1, Jeffrey E. Pessin3 and Masanobu Yamada1

1 Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan

2 Division of Biomedical Sciences, Warwick Medical School, Coventry, West Midlands, United Kingdom

3 Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, United States of America

4 Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Oxford, United Kingdom

Correspondence to:

Eijiro Yamada, email:

Keywords: Fyn, AMPK, TNFα, Autophagy

Received: March 23, 2016 Accepted: September 05, 2016 Published: September 08, 2016

Abstract

We previously demonstrated that proto-oncogene Fyn decreased energy expenditure and increased metabolic phenotypes. Also Fyn decreased autophagy-mediated 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 α 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 pro-inflammatory cytokine TNFα resulted in 1) increased Fyn activity 2) stimulated Fyn-dependent AMPKα tyrosine phosphorylation and 3) decreased AICAR-dependent AMPK activation. Importantly, TNFα induced inhibition of autophagy was not observed when AMPKα 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.


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