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Death-associated protein kinase 1 phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular

Tae Ho Lee1, Chun-Hau Chen, Futoshi Suizu

  • 1Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Molecular Cell
|April 19, 2011
PubMed

Insights

Death-associated protein kinase 1 (DAPK1) inactivates the enzyme Pin1 by phosphorylating it. This DAPK1-mediated Pin1 phosphorylation inhibits cancer-promoting activities like centrosome amplification and cell transformation.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cancer Biology

Background:

  • Pin1 is a critical regulator of signaling pathways implicated in diseases, particularly cancer.
  • The regulation of Pin1's catalytic activity, often presumed to be constitutive, remains poorly understood.

Purpose of the Study:

  • To investigate the regulatory mechanisms controlling Pin1's catalytic activity and cellular functions.
  • To identify kinases that phosphorylate and modulate Pin1 activity.

Main Methods:

  • Kinase assays to identify DAPK1 as a Pin1 kinase.
  • Site-directed mutagenesis to confirm Ser71 phosphorylation.
  • Cellular localization studies and functional assays (centrosome amplification, cell transformation).
  • Correlation analysis in human breast cancer tissues.

Main Results:

  • Death-associated protein kinase 1 (DAPK1) phosphorylates Pin1 at Ser71 within its catalytic active site.
  • Phosphorylation at Ser71 completely inactivates Pin1's catalytic activity and prevents its nuclear translocation.
  • DAPK1-mediated Pin1 inhibition reduces centrosome amplification and cell transformation.
  • Elevated Pin1 pSer71 levels correlate with higher DAPK1 levels and reduced centrosome amplification in breast cancer.

Conclusions:

  • DAPK1 acts as a negative regulator of Pin1 by phosphorylating Ser71, thereby inhibiting its enzymatic activity and oncogenic functions.
  • Pin1's catalytic activity is essential for its cellular roles, and its regulation by phosphorylation is a key mechanism.
  • This finding highlights a novel regulatory axis with potential implications for cancer therapy.

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