Fyn phosphorylates AMPK to inhibit AMPK activity and AMP-dependent activation of autophagy.
Fyn phosphorylates AMPK to inhibit AMPK activity and AMP-dependent activation of autophagy.
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DOI：
10.18632/oncotarget.11916
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发表时间：
2016-11-15
期刊：
影响因子：
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通讯作者：
Yamada M
中科院分区：
文献类型：
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作者：
Yamada E;Okada S;Bastie CC;Vatish M;Nakajima Y;Shibusawa R;Ozawa A;Pessin JE;Yamada M
我们之前证明了原癌基因Fyn降低了能量消耗并增加了代谢表型。此外，Fyn通过直接抑制LKB1和刺激STAT3活性来降低自噬介导的肌肉质量。AMPK是LKB1的下游靶点，最近被发现是控制自噬的关键分子。在这里，我们发现Fyn磷酸化Y436上AMPK的α亚基，抑制AMPK的酶活性，而不改变AMPK异三聚体复合物的组装状态。据报道，促炎介质是自噬过程的调节剂，用促炎细胞因子TNFα治疗可导致1)Fyn活性增加2)刺激Fyn依赖的AMPKα酪氨酸磷酸化3)降低aicar依赖的AMPK活化。重要的是，当AMPKα在Y436上突变时，未观察到TNFα诱导的自噬抑制。4)这些数据表明Fyn通过磷酸化和抑制AMPK介导TNFα对细胞自噬和凋亡的影响。
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.