Yamada, Eijiro, Okada, Shuichi, Bastie, Claire C., Vatish, Manu, Nakajima, Yasuyo, Shibusawa, Ryo, Ozawa, Atsushi, Pessin, Jeffrey E. and Yamada, Masanobu (2016) Fyn phosphorylates AMPK to inhibit AMPK activity and AMP-dependent activation of autophagy. Oncotarget . doi:doi:10.18632/oncotarget.11916

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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.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry Q Science > QP Physiology
Divisions:	Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Protein kinases , Pyrophosphates, Cell death
Journal or Publication Title:	Oncotarget
Publisher:	Impact Journals LLC
ISSN:	1949-2553
Official Date:	8 September 2016
Dates:	Date Event 8 September 2016 Published 5 September 2016 Accepted 23 March 2016 Submitted
Date of first compliant deposit:	13 October 2016
DOI:	doi:10.18632/oncotarget.11916
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	Nihon Gakujutsu Shinkōkai [Japan Society for the Promotion of Science] (NGS)
Grant number:	KAKENHI 25860738

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