Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop
| Autor: | David G. Campbell, Mirita Franz-Wachtel, Antje S. Löffler, Mondira Kundu, Sebastian Wesselborg, Sebastian Alers, Björn Stork, Hildegard Keppeler, Dario R. Alessi, Alexandra M. Dieterle |
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| Rok vydání: | 2011 |
| Předmět: |
mTORC1
AMP-Activated Protein Kinases Protein Serine-Threonine Kinases Biology Mice Animals Autophagy-Related Protein-1 Homolog Humans Gene Silencing Phosphorylation Protein kinase A Molecular Biology Feedback Physiological Autophagy Intracellular Signaling Peptides and Proteins AMPK Cell Biology Fibroblasts Autophagy-related protein 13 ULK1 Embryo Mammalian Cell biology Enzyme Activation Protein Subunits HEK293 Cells Gene Knockdown Techniques Protein Binding |
| Zdroj: | Autophagy. 7:696-706 |
| ISSN: | 1554-8635 1554-8627 |
| DOI: | 10.4161/auto.7.7.15451 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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