Sequential Cdk1 and Plk1 phosphorylation of protein tyrosine phosphatase 1B promotes mitotic cell death

Cell Death Dis. 2013 Jan 24;4(1):e468. doi: 10.1038/cddis.2012.208.


Mitotic cell death following prolonged arrest is an important death mechanism that is not completely understood. This study shows that Protein Tyrosine Phosphatase 1B (PTP1B) undergoes phosphorylation during mitotic arrest induced by microtubule-targeting agents (MTAs) in chronic myeloid leukaemia cells. Inhibition of cyclin-dependent kinase 1 (Cdk1) or polo-like kinase 1 (Plk1) during mitosis prevents PTP1B phosphorylation, implicating these kinases in PTP1B phosphorylation. In support of this, Cdk1 and Plk1 co-immunoprecipitate with endogenous PTP1B from mitotic cells. In addition, active recombinant Cdk1-cyclin B1 directly phosphorylates PTP1B at serine 386 in a kinase assay. Recombinant Plk1 phosphorylates PTP1B on serine 286 and 393 in vitro, however, it requires a priming phosphorylation by Cdk1 at serine 386 highlighting a novel co-operation between Cdk1 and Plk1 in the regulation of PTP1B. Furthermore, overexpression of wild-type PTP1B induced mitotic cell death, which is potentiated by MTAs. Moreover, mutation of serine 286 abrogates the cell death induced by PTP1B, whereas mutation of serine 393 does not, highlighting the importance of serine 286 phosphorylation in the execution of mitotic cell death. Finally, phosphorylation on serine 286 enhanced PTP1B phosphatase activity. Collectively, these data reveal that PTP1B activity promotes mitotic cell death and is regulated by the co-operative action of Cdk1 and Plk1 during mitotic arrest.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / toxicity
  • Apoptosis / drug effects*
  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism
  • CDC2 Protein Kinase / pharmacology*
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / pharmacology*
  • Cyclin B1 / genetics
  • Cyclin B1 / metabolism
  • Cyclin B1 / pharmacology
  • Humans
  • Immunoprecipitation
  • K562 Cells
  • Mitosis
  • Nocodazole / toxicity
  • Paclitaxel / toxicity
  • Phosphorylation / drug effects
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Serine-Threonine Kinases / pharmacology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / pharmacology*
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology
  • Serine / chemistry


  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Cyclin B1
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Serine
  • Protein Serine-Threonine Kinases
  • polo-like kinase 1
  • CDC2 Protein Kinase
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Paclitaxel
  • Nocodazole