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 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.
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
Eijiro
E
Yamada
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
Shuichi
S
Okada
Division of Biomedical Sciences, Warwick Medical School, Coventry, West Midlands, United Kingdom.
Claire C
CC
Bastie
Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Oxford, United Kingdom.
Manu
M
Vatish
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
Yasuyo
Y
Nakajima
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
Ryo
R
Shibusawa
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
Atsushi
A
Ozawa
Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
Jeffrey E
JE
Pessin
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
Masanobu
M
Yamada
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D014409:Tumor Necrosis Factor-alpha; D000249:Adenosine Monophosphate; D051076:Proto-Oncogene Proteins c-fyn; D055372:AMP-Activated Protein Kinases
AMPK; Autophagy; Fyn; TNFα