title: Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop.
abstract: 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.
authors: Department of Internal Medicine I, University of Tübingen, Tübingen, Germany.
authors: Antje S
authors: AS
authors: Löffler
authors: Sebastian
authors: S
authors: Alers
authors: Alexandra M
authors: AM
authors: Dieterle
authors: Hildegard
authors: H
authors: Keppeler
authors: Mirita
authors: M
authors: Franz-Wachtel
authors: Mondira
authors: M
authors: Kundu
authors: David G
authors: DG
authors: Campbell
authors: Sebastian
authors: S
authors: Wesselborg
authors: Dario R
authors: DR
authors: Alessi
authors: Björn
authors: B
authors: Stork
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000071189:Autophagy-Related Protein-1 Homolog; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000201:enzymology; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D021122:Protein Subunits; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human; C112444:Ulk1 protein, mouse; D055372:AMP-Activated Protein Kinases