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PLK1 (polo like kinase 1) inhibits MTOR complex 1 and promotes autophagy.

Authors
  • Ruf, Stefanie1, 2, 3, 4
  • Heberle, Alexander Martin2
  • Langelaar-Makkinje, Miriam2
  • Gelino, Sara5, 6
  • Wilkinson, Deepti5
  • Gerbeth, Carolin3, 7, 8
  • Schwarz, Jennifer Jasmin9, 10
  • Holzwarth, Birgit1
  • Warscheid, Bettina3, 9, 10
  • Meisinger, Chris3, 7, 8
  • van Vugt, Marcel A T M11
  • Baumeister, Ralf1, 3, 4, 7, 10
  • Hansen, Malene5
  • Thedieck, Kathrin2, 12
  • 1 a Department of Bioinformatics and Molecular Genetics , Faculty of Biology, University of Freiburg , 79104 Freiburg , Germany.
  • 2 b Department of Pediatrics , Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen , 9713 AV Groningen , The Netherlands.
  • 3 c BIOSS Centre for Biological Signalling Studies, University of Freiburg.
  • 4 d Research Training Group (RTG) 1104, University of Freiburg.
  • 5 e Program of Development, Aging and Regeneration, Sanford Burnham Prebys Medical Discovery Institute , La Jolla , 92037 CA , USA.
  • 6 f Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute , La Jolla , 92037 CA , USA.
  • 7 g ZBMZ Centre for Biochemistry and Molecular Cell Research (Faculty of Medicine), University of Freiburg.
  • 8 h Institute of Biochemistry and Molecular Biology (Faculty of Medicine), University of Freiburg.
  • 9 i Department of Biochemistry and Functional Proteomics , Faculty of Biology, University of Freiburg.
  • 10 j Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg.
  • 11 k Department of Medical Oncology , Cancer Research Center Groningen, University of Groningen, University Medical Center Groningen , 9723 GZ Groningen , The Netherlands.
  • 12 l Department for Neuroscience , School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg , 26129 Oldenburg , Germany.
Type
Published Article
Journal
Autophagy
Publisher
Landes Bioscience
Publication Date
Jan 19, 2017
Identifiers
DOI: 10.1080/15548627.2016.1263781
PMID: 28102733
Source
Medline
Keywords
License
Unknown

Abstract

Mechanistic target of rapamycin complex 1 (MTORC1) and PLK1 (polo like kinase 1) are major drivers of cancer cell growth and proliferation, and inhibitors of both protein kinases are currently being investigated in clinical studies. To date, MTORC1's and PLK1's functions are mostly studied separately, and reports on their mutual crosstalk are scarce. Here, we identify PLK1 as a physical MTORC1 interactor in human cancer cells. PLK1 inhibition enhances MTORC1 activity under nutrient sufficiency and in starved cells, and PLK1 directly phosphorylates the MTORC1 component RPTOR/RAPTOR in vitro. PLK1 and MTORC1 reside together at lysosomes, the subcellular site where MTORC1 is active. Consistent with an inhibitory role of PLK1 toward MTORC1, PLK1 overexpression inhibits lysosomal association of the PLK1-MTORC1 complex, whereas PLK1 inhibition promotes lysosomal localization of MTOR. PLK1-MTORC1 binding is enhanced by amino acid starvation, a condition known to increase autophagy. MTORC1 inhibition is an important step in autophagy activation. Consistently, PLK1 inhibition mitigates autophagy in cancer cells both under nutrient starvation and sufficiency, and a role of PLK1 in autophagy is also observed in the invertebrate model organism Caenorhabditis elegans. In summary, PLK1 inhibits MTORC1 and thereby positively contributes to autophagy. Since autophagy is increasingly recognized to contribute to tumor cell survival and growth, we propose that cautious monitoring of MTORC1 and autophagy readouts in clinical trials with PLK1 inhibitors is needed to develop strategies for optimized (combinatorial) cancer therapies targeting MTORC1, PLK1, and autophagy.

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