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LATS1/WARTS phosphorylates MYPT1 to counteract PLK1 and regulate mammalian mitotic progression

Tatsuyuki Chiyoda1, Naoyuki Sugiyama, Takatsune Shimizu

  • 1Division of Gene Regulation, Institute for Advanced Medical Research, Department of Obstetrics and Gynecology, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.

The Journal of Cell Biology
|May 30, 2012
PubMed

Insights

Large tumor suppressor kinase 1 (LATS1) phosphorylates myosin phosphatase-targeting subunit 1 (MYPT1), antagonizing polo-like kinase 1 (PLK1) activity. This LATS1-MYPT1 interaction is crucial for the G2 DNA damage checkpoint.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Dbf2 kinase regulates Cdc14 phosphatase in yeast mitotic exit.
  • No phosphatase substrates for the mammalian LATS1 kinase, Dbf2's equivalent, were previously identified.
  • Understanding LATS1 function is critical for cell cycle regulation and cancer research.

Purpose of the Study:

  • To identify phosphatase substrates of LATS1 kinase.
  • To elucidate the role of LATS1 in regulating polo-like kinase 1 (PLK1) activity.
  • To investigate LATS1's function in the G2 DNA damage checkpoint.

Main Methods:

  • Phosphoproteomic screening to identify LATS1 kinase substrates.
  • Site-directed mutagenesis to create MYPT1 S445A mutant.
  • Western blotting and cell-based assays using LATS1-depleted cells and LATS1 knockout mouse fibroblasts.
  • Analysis of G2 checkpoint arrest following DNA damage.

Main Results:

  • Myosin phosphatase-targeting subunit 1 (MYPT1) was identified as a novel LATS1 substrate, phosphorylated at serine 445 (S445).
  • LATS1-mediated phosphorylation of MYPT1 S445 antagonizes polo-like kinase 1 (PLK1) activity.
  • LATS1 depletion or knockout increased PLK1 activity and impaired G2 DNA damage checkpoint arrest.

Conclusions:

  • LATS1 phosphorylates MYPT1, a phosphatase, mirroring yeast Dbf2's function.
  • LATS1 plays a novel role in suppressing PLK1 activity via MYPT1 phosphorylation.
  • LATS1 is essential for maintaining the G2 DNA damage checkpoint integrity.

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