title: PAK6 targets to cell-cell adhesions through its N-terminus in a Cdc42-dependent manner to drive epithelial colony escape.
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.
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Morse
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jordan R
authors.initials: JR
authors.lastname: Olberding
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Byung Hak
authors.initials: BH
authors.lastname: Ha
authors.affiliation: 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.
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.affiliation: 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.
authors.forename: David A
authors.initials: DA
authors.lastname: Calderwood
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007365:Intercellular Junctions / Q000201:enzymology; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021382:Protein Sorting Signals; D021381:Protein Transport; D020764:cdc42 GTP-Binding Protein / Q000502:physiology*; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D021382:Protein Sorting Signals; C429007:PAK6 protein, human; D054462:p21-Activated Kinases; D020764:cdc42 GTP-Binding Protein
keywords: Cdc42; Cell–cell adhesions; PAK6; p21-activated kinase