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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Antigens, CD
  • Cadherins / metabolism
  • Cell Adhesion
  • Cell Line, Tumor
  • Epithelial Cells / physiology*
  • HEK293 Cells
  • Humans
  • Intercellular Junctions / enzymology
  • Molecular Sequence Data
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Sorting Signals
  • Protein Transport
  • cdc42 GTP-Binding Protein / physiology*
  • p21-Activated Kinases / metabolism*

Substances

  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • Protein Sorting Signals
  • PAK6 protein, human
  • p21-Activated Kinases
  • cdc42 GTP-Binding Protein