The serine/threonine kinase ULK1 is a target of multiple phosphorylation events

Markus Bach, Mark Larance, David James, Georg Ramm

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125 Citations (Scopus)

Abstract

Autophagy is a cellular degradation process that is up regulated upon starvation. Nutrition-dependent regulation of mTOR is a major determinant of autophagy. RTK signalling and AMPK converge upon mTOR to suppress or activate autophagy. Nutrition-dependent regulation of autophagy is mediated via mTOR phosphorylation of the Ser/Thr kinase ULK1. In this study we also describe ULK1 as an mTOR-independent convergence point for AMPK and RTK signalling. We initially identified ULK1 as a 14-3-3 binding protein and this interaction was enhanced by treatment with AMPK agonists. AMPK interacted with ULK1 and phosphorylated ULK1 at Ser555 in vitro. Mutation of this residue to Ala abrogated 14-3-3 binding to ULK1 and in vivo phosphorylation of ULK1 was blocked by a dominant negative AMPK mutant. We next identified a high stringency Akt site in ULK1 at Ser774 and showed that phosphorylation at this site was increased by insulin. Finally, we found that the kinase activation loop of ULK1 contains a consensus phosphorylation site at Thr180 that is required for ULK1 autophosphorylation activity. Collectively, our data suggest that ULK1 may act as a major node for regulation by multiple kinases including AMPK and Akt that play both stimulatory and inhibitory roles in regulating autophagy.
Original languageEnglish
Pages (from-to)283 - 291
Number of pages9
JournalBiochemical Journal
Volume440
Issue number2
DOIs
Publication statusPublished - 2011

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