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J Cell Sci. 2016 Jan 15;129(2):380-93. doi: 10.1242/jcs.177493. Epub 2015 Nov 23.

PAK6 targets to cell-cell adhesions through its N-terminus in a Cdc42-dependent manner to drive epithelial colony escape.

Author information

1
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
3
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA.
4
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA david.calderwood@yale.edu.

Abstract

The six serine/threonine kinases in the p21-activated kinase (PAK) family are important regulators of cell adhesion, motility and survival. PAK6, which is overexpressed in prostate cancer, was recently reported to localize to cell-cell adhesions and to drive epithelial cell colony escape. Here we report that PAK6 targeting to cell-cell adhesions occurs through its N-terminus, requiring both its Cdc42/Rac interactive binding (CRIB) domain and an adjacent polybasic region for maximal targeting efficiency. We find PAK6 localization to cell-cell adhesions is Cdc42-dependent, as Cdc42 knockdown inhibits PAK6 targeting to cell-cell adhesions. We further find the ability of PAK6 to drive epithelial cell colony escape requires kinase activity and is disrupted by mutations that perturb PAK6 cell-cell adhesion targeting. Finally, we demonstrate that all type II PAKs (PAK4, PAK5 and PAK6) target to cell-cell adhesions, albeit to differing extents, but PAK1 (a type I PAK) does not. Notably, the ability of a PAK isoform to drive epithelial colony escape correlates with its targeting to cell-cell adhesions. We conclude that PAKs have a broader role in the regulation of cell-cell adhesions than previously appreciated.

KEYWORDS:

Cdc42; Cell–cell adhesions; PAK6; p21-activated kinase

PMID:
26598554
PMCID:
PMC4732285
DOI:
10.1242/jcs.177493
[Indexed for MEDLINE]
Free PMC Article

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