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

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...

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Bibliographic Details
Published in:Oncotarget 2016-11, Vol.7 (46), p.74612-74629
Main Authors: Yamada, Eijiro, Okada, Shuichi, Bastie, Claire C, Vatish, Manu, Nakajima, Yasuyo, Shibusawa, Ryo, Ozawa, Atsushi, Pessin, Jeffrey E, Yamada, Masanobu
Format: Article
Language:English
Subjects:
Adenosine Monophosphate - metabolism
AMP-Activated Protein Kinases - genetics
AMP-Activated Protein Kinases - metabolism
Animals
Apoptosis - drug effects
Apoptosis - genetics
Autophagy - drug effects
Autophagy - genetics
Cell Line
Enzyme Activation
Humans
Mice
Muscle, Skeletal - drug effects
Muscle, Skeletal - metabolism
Phosphorylation
Proto-Oncogene Proteins c-fyn - genetics
Proto-Oncogene Proteins c-fyn - metabolism
Research Paper: Autophagy and Cell Death
Stress, Physiological - drug effects
Tumor Necrosis Factor-alpha - metabolism
Tumor Necrosis Factor-alpha - pharmacology
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.11916