title: A PAK6-IQGAP1 complex promotes disassembly of cell-cell adhesions.
abstract: p-21 activated 6 (PAK6), first identified as interacting with the androgen receptor (AR), is over-expressed in multiple cancer tissues and has been linked to the progression of prostate cancer, however little is known about PAK6 function in the absence of AR signaling. We report here that PAK6 is specifically required for carcinoma cell-cell dissociation downstream of hepatocyte growth factor (HGF) for both DU145 prostate cancer and HT29 colon cancer cells. Moreover, PAK6 overexpression can drive cells to escape from adhesive colonies in the absence of stimulation. We have localized PAK6 to cell-cell junctions and have detected a direct interaction between the kinase domain of PAK6 and the junctional protein IQGAP1. Co-expression of IQGAP1 and PAK6 increases cell colony escape and leads to elevated PAK6 activation. Further studies have identified a PAK6/E-cadherin/IQGAP1 complex downstream of HGF. Moreover, we find that β-catenin is also localized with PAK6 in cell-cell junctions and is a novel PAK6 substrate. We propose a unique role for PAK6, independent of AR signaling, where PAK6 drives junction disassembly during HGF-driven cell-cell dissociation via an IQGAP1/E-cadherin complex that leads to the phosphorylation of β-catenin and the disruption of cell-cell adhesions.
authors.affiliation: Division of Cancer Studies, King's College London, New Hunts House, Guys Campus, London, SE1 1UL, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Fram
authors.forename: Helen
authors.initials: H
authors.lastname: King
authors.forename: David B
authors.initials: DB
authors.lastname: Sacks
authors.forename: Claire M
authors.initials: CM
authors.lastname: Wells
mesh_terms: D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism*; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D051176:beta Catenin / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism / Q000502:physiology*; D020703:ras GTPase-Activating Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: C101203:IQ motif containing GTPase activating protein 1; D051176:beta Catenin; D020703:ras GTPase-Activating Proteins; C429007:PAK6 protein, human; D054462:p21-Activated Kinases