The Cdc42 effector kinase PAK4 localizes to cell-cell junctions and contributes to establishing cell polarity
Selamat W. ; Tay P.-L.F. ; Baskaran Y. ; Manser E.
Selamat W.
Tay P.-L.F.
Baskaran Y.
Citations
Altmetric:
Alternative Title
Abstract
The serine/threonine kinase PAK4 is a Cdc42 effector whose role is not well understood; overexpression of PAK4 has been associated with some cancers, and there are reports that correlate kinase level with increased cell migration in vitro. Here we report that PAK4 is primarily associated with cell-cell junctions in all the cell lines we tested, and fails to accumulate at focal adhesions or at the leading edge of migrating cells. In U2OS osteosarcoma and MCF-7 breast cancer cell lines, PAK4 depletion did not affect collective cell migration, but affected cell polarization. By contrast, Cdc42 depletion (as reported by many studies) caused a strong defect in junctional assembly in multiple cells lines. We also report that the depletion of PAK4 protein or treatment of cells with the PAK4 inhibitor PF-3758309 can lead to defects in centrosome reorientation (polarization) after cell monolayer wounding. These experiments are consistent with PAK4 forming part of a conserved cell-cell junctional polarity Cdc42 complex. We also confirm ?-catenin as a target for PAK4 in these cells. Treatment of cells with PF-3758309 caused inhibition of ?-catenin Ser-675 phosphorylation, which is located predominantly at cell-cell junctions. © 2015 Selamat et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords
beta catenin, p21 activated kinase 4, protein Cdc42, protein serine threonine kinase inhibitor, serine, beta catenin, CTNNB1 protein, human, p21 activated kinase, PAK4 protein, human, PF 3758309, protein Cdc42, protein kinase inhibitor, pyrazole derivative, pyrrole derivative, serine, animal cell, Article, cell junction, cell migration, cell polarity, centrosome, complex formation, focal adhesion, human, human cell, MCF 7 cell line, monolayer culture, nonhuman, protein assembly, protein depletion, protein localization, protein phosphorylation, U2OS cell line, wound, antagonists and inhibitors, cell junction, drug effects, gene silencing, genetics, MCF-7 cell line, metabolism, phosphorylation, tumor cell line, beta Catenin, cdc42 GTP-Binding Protein, Cell Line, Tumor, Cell Polarity, Gene Knockdown Techniques, Humans, Intercellular Junctions, MCF-7 Cells, p21-Activated Kinases, Phosphorylation, Protein Kinase Inhibitors, Pyrazoles, Pyrroles, Serine
Source Title
PLoS ONE
Publisher
Series/Report No.
Collections
Rights
Attribution 4.0 International
Date
2015
DOI
10.1371/journal.pone.0129634
Type
Article