JOURNAL ARTICLE

Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop

Antje S Löffler, Sebastian Alers, Alexandra M Dieterle, Hildegard Keppeler, Mirita Franz-Wachtel, Mondira Kundu, David G Campbell, Sebastian Wesselborg, Dario R Alessi, Björn Stork
Autophagy 2011, 7 (7): 696-706
21460634
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 (FIP 200). 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.

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