Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop
Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop
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DOI：
10.4161/auto.7.7.15451
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发表时间：
2011-07-01
期刊：
影响因子：
13.3
通讯作者：
Stork, Bjoern
中科院分区：
文献类型：
--
作者：
Loeffler, Antje S.;Alers, Sebastian;Stork, Bjoern
Unc-51样激酶1（Ulk 1）在自噬诱导中起着重要作用。它与Atg 13和200 kDa的粘着斑激酶（FAK）家族相互作用蛋白（FIP 200）形成稳定的复合物。这种复合物是负调控的哺乳动物靶雷帕霉素复合物1（mTORC 1）在营养依赖性的方式。AMP激活的蛋白激酶（AMPK）在高AMP水平时被LKB 1/Strad/Mo 25激活，通过抑制mTORC 1刺激自噬。最近，已经描述了AMPK和Ulk 1相互作用，并且后者被AMPK磷酸化。这种磷酸化导致AMPK绕过mTOR抑制直接激活Ulk 1。在这里，我们报告说，Ulk 1/2反过来磷酸化AMPK的所有三个亚基，从而负调控其活性。因此，我们认为Ulk 1不仅参与了自噬的诱导，而且还参与了终止触发自噬的信号事件。在我们的模型中，AMPK被Ulk 1磷酸化代表了一个负反馈回路。
Unc-51-like kinase 1 (Ulk1) plays a central role in autophagy induction. It forms a stable complex with Atg13 and focal adhesion kinase (FAK) family interacting protein of 200 kDa (FIP200). This complex is negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1) in a nutrient-dependent way. AMP-activated protein kinase (AMPK), which is activated by LKB1/Strad/Mo25 upon high AMP levels, stimulates autophagy by inhibiting mTORC1. Recently, it has been described that AMPK and Ulk1 interact and that the latter is phosphorylated by AMPK. This phosphorylation leads to the direct activation of Ulk1 by AMPK bypassing mTOR-inhibition. Here we report that Ulk1/2 in turn phosphorylates all three subunits of AMPK and thereby negatively regulates its activity. Thus, we propose that Ulk1 is not only involved in the induction of autophagy, but also in terminating signaling events that trigger autophagy. In our model, phosphorylation of AMPK by Ulk1 represents a negative feedback circuit.