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Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase

Hongchuan Jin1, Tobias Sperka, Peter Herrlich

  • 1Leibniz Institute of Age Research-Fritz-Lipmann-Institute, Beutenbergstrasse 11, 07745 Jena, Germany.

Nature
|August 4, 2006
PubMed

Insights

The myosin phosphatase (MYPT-1-PP1delta) activates the tumor suppressor merlin by dephosphorylation. Its inhibitor, CPI-17, promotes cancer by disrupting this merlin pathway, highlighting a new tumor suppressor cascade.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Merlin (neurofibromatosis type 2 gene NF2) is a tumor suppressor regulating cell proliferation.
  • Merlin activation requires dephosphorylation at serine 518 (S518), but the responsible phosphatase was unknown.

Purpose of the Study:

  • To identify the phosphatase that activates merlin's tumor suppressor function.
  • To investigate the role of this phosphatase and its inhibitor in cancer.

Main Methods:

  • Enzyme identification assays.
  • Cellular assays using merlin mutants and CPI-17 inhibitor.
  • Analysis of CPI-17 levels in human tumor cell lines.

Main Results:

  • Myosin phosphatase (MYPT-1-PP1delta) was identified as the merlin-activating phosphatase.
  • The MYPT-1-PP1delta-specific inhibitor CPI-17 causes merlin phosphorylation, Ras activation, and cell transformation.
  • Downregulation of CPI-17 reversed these oncogenic effects, confirming merlin as the key substrate.

Conclusions:

  • MYPT-1-PP1delta and merlin form a novel tumor suppressor cascade.
  • This cascade can be disrupted by NF2 mutations or increased CPI-17 levels, contributing to tumorigenesis.

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