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The Cdc42 Effector Kinase PAK4 Localizes to Cell-Cell Junctions and Contributes to Establishing Cell Polarity

Widyawilis Selamat1, Pei-Ling Felicia Tay1, Yohendran Baskaran1

  • 1small G-protein Signaling and Kinases (sGSK) Group, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.

Plos One
|June 13, 2015
PubMed

Insights

The serine/threonine kinase PAK4 localizes to cell-cell junctions and regulates cell polarization, not migration. PAK4 inhibition disrupts centrosome reorientation and beta-catenin phosphorylation at junctions.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The serine/threonine kinase PAK4 is a Cdc42 effector with an unclear role, though its overexpression is linked to cancers and increased cell migration.
  • Previous studies suggest a correlation between PAK4 levels and enhanced cell migration in vitro.

Purpose of the Study:

  • To investigate the precise role of PAK4 in cell migration, polarization, and its association with cell-cell junctions.
  • To identify downstream targets of PAK4 and its function in the context of Cdc42 signaling.

Main Methods:

  • Utilized cell lines (U2OS, MCF-7) for PAK4 and Cdc42 depletion experiments.
  • Employed PAK4 inhibitor PF-3758309 to assess effects on cell migration, polarization, and centrosome reorientation.
  • Confirmed beta-catenin as a PAK4 target by examining its phosphorylation status.

Main Results:

  • PAK4 predominantly localizes to cell-cell junctions, not focal adhesions or leading edges.
  • PAK4 depletion did not impair collective cell migration but affected cell polarization.
  • PAK4 depletion or inhibition led to defects in centrosome reorientation and inhibited beta-catenin Ser-675 phosphorylation at cell-cell junctions.

Conclusions:

  • PAK4 is a component of a conserved cell-cell junctional polarity Cdc42 complex, regulating cell polarization.
  • PAK4's primary role appears to be in cell polarity rather than direct promotion of cell migration.
  • PAK4 directly targets beta-catenin for phosphorylation at cell-cell junctions, impacting polarity mechanisms.

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