title: PLK1 (polo like kinase 1) inhibits MTOR complex 1 and promotes autophagy.
abstract: Mechanistic target of rapamycin complex 1 (MTORC1) and polo like kinase 1 (PLK1) 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.
authors.affiliation: a Department of Bioinformatics and Molecular Genetics, Faculty of Biology , University of Freiburg , Freiburg , Germany.|b Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases , University of Groningen, University Medical Center Groningen , AV Groningen , The Netherlands.|c BIOSS Centre for Biological Signalling Studies , University of Freiburg , Freiburg , Germany.|d Research Training Group (RTG) 1104 , University of Freiburg , Freiburg , Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Ruf
authors.affiliation: b Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases , University of Groningen, University Medical Center Groningen , AV Groningen , The Netherlands.
authors.forename: Alexander Martin
authors.initials: AM
authors.lastname: Heberle
authors.affiliation: b Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases , University of Groningen, University Medical Center Groningen , AV Groningen , The Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Langelaar-Makkinje
authors.affiliation: e Program of Development, Aging and Regeneration , Sanford Burnham Prebys Medical Discovery Institute , La Jolla , CA , USA.|f Graduate School of Biomedical Sciences , Sanford Burnham Prebys Medical Discovery Institute , La Jolla , CA , USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Gelino
authors.affiliation: e Program of Development, Aging and Regeneration , Sanford Burnham Prebys Medical Discovery Institute , La Jolla , CA , USA.
authors.forename: Deepti
authors.initials: D
authors.lastname: Wilkinson
authors.affiliation: c BIOSS Centre for Biological Signalling Studies , University of Freiburg , Freiburg , Germany.|g ZBMZ Centre for Biochemistry and Molecular Cell Research (Faculty of Medicine) , University of Freiburg , Freiburg , Germany.|h Institute of Biochemistry and Molecular Biology (Faculty of Medicine), University of Freiburg , Freiburg , Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Gerbeth
authors.affiliation: i Department of Biochemistry and Functional Proteomics, Faculty of Biology , University of Freiburg , Freiburg , Germany.|j Spemann Graduate School of Biology and Medicine (SGBM) , University of Freiburg , Freiburg , Germany.
authors.forename: Jennifer Jasmin
authors.initials: JJ
authors.lastname: Schwarz
authors.affiliation: a Department of Bioinformatics and Molecular Genetics, Faculty of Biology , University of Freiburg , Freiburg , Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Holzwarth
authors.affiliation: c BIOSS Centre for Biological Signalling Studies , University of Freiburg , Freiburg , Germany.|i Department of Biochemistry and Functional Proteomics, Faculty of Biology , University of Freiburg , Freiburg , Germany.|j Spemann Graduate School of Biology and Medicine (SGBM) , University of Freiburg , Freiburg , Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Warscheid
authors.affiliation: c BIOSS Centre for Biological Signalling Studies , University of Freiburg , Freiburg , Germany.|g ZBMZ Centre for Biochemistry and Molecular Cell Research (Faculty of Medicine) , University of Freiburg , Freiburg , Germany.|h Institute of Biochemistry and Molecular Biology (Faculty of Medicine), University of Freiburg , Freiburg , Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Meisinger
authors.affiliation: k Department of Medical Oncology, Cancer Research Center Groningen , University of Groningen, University Medical Center Groningen , GZ Groningen , The Netherlands.
authors.forename: Marcel A T M
authors.initials: MA
authors.lastname: van Vugt
authors.affiliation: a Department of Bioinformatics and Molecular Genetics, Faculty of Biology , University of Freiburg , Freiburg , Germany.|c BIOSS Centre for Biological Signalling Studies , University of Freiburg , Freiburg , Germany.|d Research Training Group (RTG) 1104 , University of Freiburg , Freiburg , Germany.|g ZBMZ Centre for Biochemistry and Molecular Cell Research (Faculty of Medicine) , University of Freiburg , Freiburg , Germany.|j Spemann Graduate School of Biology and Medicine (SGBM) , University of Freiburg , Freiburg , Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Baumeister
authors.affiliation: e Program of Development, Aging and Regeneration , Sanford Burnham Prebys Medical Discovery Institute , La Jolla , CA , USA.
authors.forename: Malene
authors.initials: M
authors.lastname: Hansen
authors.affiliation: b Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases , University of Groningen, University Medical Center Groningen , AV Groningen , The Netherlands.|l Department for Neuroscience, School of Medicine and Health Sciences , Carl von Ossietzky University Oldenburg , Oldenburg , Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Thedieck
mesh_terms: D000596:Amino Acids / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D015415:Biomarkers / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007399:Interphase; D008247:Lysosomes / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D008938:Mitosis; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000076223:Regulatory-Associated Protein of mTOR / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D000596:Amino Acids; D015415:Biomarkers; D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000076223:Regulatory-Associated Protein of mTOR; D058570:TOR Serine-Threonine Kinases; D000097869:Polo-Like Kinase 1; C463659:RPTOR protein, human; C513017:plk-1 protein, C elegans
keywords: BI2536; MTOR; MTORC1; PLK1; RPTOR; amino acid; insulin; interphase; lysosome; starvation