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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Research Article|
November 14 2011
The serine/threonine kinase ULK1 is a target of multiple phosphorylation events
Markus Bach;
Markus Bach
*Department of Biochemistry and Molecular Biology and Monash Micro Imaging, School of Biomedical Sciences, Monash University, Melbourne, VIC 3800, Australia
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Mark Larance;
Mark Larance
1
†Diabetes and Obesity Research Program, The Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
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David E. James;
David E. James
†Diabetes and Obesity Research Program, The Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
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Georg Ramm
Georg Ramm
2
*Department of Biochemistry and Molecular Biology and Monash Micro Imaging, School of Biomedical Sciences, Monash University, Melbourne, VIC 3800, Australia
†Diabetes and Obesity Research Program, The Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
2To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
November 22 2010
Revision Received:
August 04 2011
Accepted:
August 05 2011
Accepted Manuscript online:
August 05 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 440 (2): 283–291.
Article history
Received:
November 22 2010
Revision Received:
August 04 2011
Accepted:
August 05 2011
Accepted Manuscript online:
August 05 2011
Citation
Markus Bach, Mark Larance, David E. James, Georg Ramm; The serine/threonine kinase ULK1 is a target of multiple phosphorylation events. Biochem J 1 December 2011; 440 (2): 283–291. doi: https://doi.org/10.1042/BJ20101894
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