Plk1 protein phosphorylates phosphatase and tensin homolog (PTEN) and regulates its mitotic activity during the cell cycle.
PTEN is a well known tumor suppressor through the negative regulation of the PI3K signaling pathway. Here we report that PTEN plays an important role in regulating mitotic timing, which is associated with increased PTEN phosphorylation in the C-terminal tail and its localization to chromatin. Pulldown analysis revealed that Plk1 physically interacted with PTEN. Biochemical studies showed that Plk1 phosphorylates PTEN in vitro in a concentration-dependent manner and that the phosphorylation was inhibited by Bi2635, a Plk1-specific inhibitor. Deletional and mutational analyses identified that Plk1 phosphorylated Ser-380, Thr-382, and Thr-383, but not Ser-385, a cluster of residues known to affect the PTEN stability. Interestingly, a combination of molecular and genetic analyses revealed that only Ser-380 was significantly phosphorylated in vivo and that Plk1 regulated the phosphorylation, which was associated with the accumulation of PTEN on chromatin. Moreover, expression of phospho-deficient mutant, but not wild-type PTEN, caused enhanced mitotic exit. Taken together, our studies identify Plk1 as an important regulator of PTEN during the cell cycle.
From the Departments of Environmental Medicine, Biochemistry, and Molecular Pharmacology, New York University School of Medicine, Tuxedo, New York 10987.
Byeong Hyeok
BH
Choi
the Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, New York 10016, and the Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016.
Michele
M
Pagano
From the Departments of Environmental Medicine, Biochemistry, and Molecular Pharmacology, New York University School of Medicine, Tuxedo, New York 10987, wei.dai@nyumc.org.
Wei
W
Dai
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008938:Mitosis; D051059:PTEN Phosphohydrolase / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D002843:Chromatin; D051059:PTEN Phosphohydrolase; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012694:Serine; D000097869:Polo-Like Kinase 1
Cell Cycle; Cell Signaling; Chromatin; Kinase; Mitosis; PTEN; Phosphorylation; Plk1