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

D S O'Donovan1, S MacFhearraigh, J Whitfield

  • 1UCD School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.

Cell Death & Disease
|January 26, 2013
PubMed

Insights

Protein Tyrosine Phosphatase 1B (PTP1B) phosphorylation during mitotic arrest, regulated by Cdk1 and Plk1 kinases, promotes cell death. This study reveals a novel mechanism for mitotic cell death execution.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Mitotic cell death is a crucial process following prolonged cell cycle arrest.
  • The precise mechanisms regulating mitotic cell death remain incompletely understood.
  • Protein Tyrosine Phosphatase 1B (PTP1B) is implicated in cellular processes, but its role in mitotic death is unclear.

Purpose of the Study:

  • To investigate the role of PTP1B phosphorylation during mitotic arrest.
  • To identify kinases regulating PTP1B phosphorylation during mitosis.
  • To elucidate the contribution of PTP1B to mitotic cell death.

Main Methods:

  • Utilized chronic myeloid leukaemia cells undergoing mitotic arrest induced by microtubule-targeting agents (MTAs).
  • Employed co-immunoprecipitation and in vitro kinase assays to study protein interactions and phosphorylation.
  • Generated site-specific PTP1B mutants to assess the functional significance of phosphorylation sites.

Main Results:

  • PTP1B undergoes phosphorylation during mitotic arrest, regulated by cyclin-dependent kinase 1 (Cdk1) and polo-like kinase 1 (Plk1).
  • Cdk1 and Plk1 cooperate to phosphorylate PTP1B at specific serine residues (S386 by Cdk1, S286/S393 by Plk1).
  • Overexpression of wild-type PTP1B induces mitotic cell death, enhanced by MTAs, with S286 phosphorylation being critical for this effect and increasing PTP1B activity.

Conclusions:

  • PTP1B activity promotes mitotic cell death.
  • Cdk1 and Plk1 cooperatively regulate PTP1B phosphorylation during mitotic arrest.
  • Phosphorylation of PTP1B at serine 286 is essential for mediating MTA-induced mitotic cell death.

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