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

Bach, Markus, Larance, Mark, James, David E., Ramm, Georg·2011·Biochemical Journal
DOI 10.1042/bj20101894
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Abstract

Autophagy is a cellular degradation process that is up-regulated upon starvation. Nutrition-dependent regulation of mTOR (mammalian target of rapamycin) is a major determinant of autophagy. RTK (receptor tyrosine kinase) signalling and AMPK (AMP-activated protein kinase) converge upon mTOR to suppress or activate autophagy. Nutrition-dependent regulation of autophagy is mediated via mTOR phosphorylation of the serine/threonine kinase ULK1 (unc51-like kinase 1). In the present 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 Ser555in vitro. Mutation of this residue to alanine 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 results 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.

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Metadata

Authors
Bach, M., Larance, M., James, D. E., & Ramm, G.
Venue
Biochemical Journal
Publisher
Portland Press Ltd.
Published
2011-11-14
Volume
440
Issue
2
Pages
283-291
ISSN
  • 0264-6021
  • 1470-8728
DOI
10.1042/bj20101894
Cited by
233
References
10
Language
en

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