title: Plk1 phosphorylation of PTEN causes a tumor-promoting metabolic state.
abstract: One outcome of activation of the phosphatidylinositol 3-kinase (PI3K) pathway is increased aerobic glycolysis, but the upstream signaling events that regulate the PI3K pathway, and thus the Warburg effect, are elusive. Increasing evidence suggests that Plk1, a cell cycle regulator, is also involved in cellular events in addition to mitosis. To test whether Plk1 contributes to activation of the PI3K pathway, and thus aerobic glycolysis, we examined potential targets of Plk1 and identified PTEN as a Plk1 substrate. We hypothesize that Plk1 phosphorylation of PTEN leads to its inactivation, activation of the PI3K pathway, and the Warburg effect. Our data show that overexpression of Plk1 leads to activation of the PI3K pathway and enhanced aerobic glycolysis. In contrast, inhibition of Plk1 causes markedly reduced glucose metabolism in mice. Mechanistically, we show that Plk1 phosphorylation of PTEN and Nedd4-1, an E3 ubiquitin ligase of PTEN, results in PTEN inactivation. Finally, we show that Plk1 phosphorylation of PTEN promotes tumorigenesis in both its phosphatase-dependent and -independent pathways, revealing potentially new drug targets to arrest tumor cell growth.
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Pengpeng
authors.initials: P
authors.lastname: Bi
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Grant
authors.initials: G
authors.lastname: Burcham
authors.affiliation: Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Bennett D
authors.initials: BD
authors.lastname: Elzey
authors.affiliation: Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, USA Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Ratliff
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Konieczny
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Nihal
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Shihuan
authors.initials: S
authors.lastname: Kuang
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, Indiana, USA Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA liu8@purdue.edu.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology; D057809:HEK293 Cells; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D000075702:Nedd4 Ubiquitin Protein Ligases; D009374:Neoplasms, Experimental; D015739:Nocodazole / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011621:Pteridines; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018797:Cell Cycle Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D005947:Glucose; D006574:Heterocyclic Compounds, 2-Ring; D019344:Lactic Acid; D000075702:Nedd4 Ubiquitin Protein Ligases; D015739:Nocodazole; D051059:PTEN Phosphohydrolase; D058539:Phosphatidylinositol 3-Kinase; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D044767:Ubiquitin-Protein Ligases; D000097869:Polo-Like Kinase 1; C518477:BI 2536; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse