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Mst4 and Ezrin induce brush borders downstream of the Lkb1/Strad/Mo25 polarization complex

Jean Paul ten Klooster1, Marnix Jansen, Jin Yuan

  • 1Hubrecht Institute, KNAW and University Medical Centre, Utrecht, The Netherlands.

Developmental Cell
|April 24, 2009
PubMed

Insights

The Lkb1/Strad/Mo25 complex initiates intestinal cell polarization. This study identifies Mst4 kinase as a key downstream effector, crucial for brush border formation by phosphorylating Ezrin.

Area of Science:

  • Cell biology
  • Molecular biology
  • Cancer biology

Background:

  • The Lkb1 kinase, an ortholog of the invertebrate Par4 polarity gene, is implicated in Peutz-Jeghers cancer syndrome.
  • Lkb1 functions in a complex with pseudokinase Strad and adaptor protein Mo25 to induce epithelial cell polarization.
  • This complex can drive complete polarization in isolated intestinal epithelial cells.

Purpose of the Study:

  • To investigate the downstream signaling pathway of the Lkb1/Strad/Mo25 complex in epithelial cell polarity.
  • To identify novel components involved in Lkb1-mediated brush border formation.
  • To elucidate the role of Mst4 kinase in epithelial cell polarity.

Main Methods:

  • Co-immunoprecipitation to identify protein interactions.
  • Cellular localization studies using microscopy.
  • Functional assays to assess the impact of Mst4 inhibition on cell polarity.
  • In vitro kinase assays to determine Mst4 phosphorylation targets.

Main Results:

  • An interaction between Mo25alpha and the serine/threonine kinase Mst4 was identified, conserved in yeast.
  • Human Mst4 translocates to the subapical membrane upon Lkb1 activation.
  • Inhibition of Mst4 impairs Lkb1-induced brush border formation but not lateral junction formation.
  • Mst4 phosphorylates Ezrin at residue T567, a critical step in brush border assembly.

Conclusions:

  • A novel pathway for brush border induction downstream of the Lkb1/Strad/Mo25 complex is defined.
  • Mst4 acts as a key effector kinase in this pathway, distinct from other polarity mechanisms.
  • This finding provides new insights into the regulation of epithelial cell polarity and its disruption in cancer.

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