A PAK6-IQGAP1 complex promotes disassembly of cell-cell adhesions

TY - JOUR

T1 - A PAK6-IQGAP1 complex promotes disassembly of cell-cell adhesions

AU - Fram, Sally

AU - King, Helen

AU - Sacks, David B.

AU - Wells, Claire M.

PY - 2014/7

Y1 - 2014/7

N2 - 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 beta-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 beta-catenin and the disruption of cell-cell adhesions.

AB - 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 beta-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 beta-catenin and the disruption of cell-cell adhesions.

KW - PAK6

KW - IQGAP

KW - Cell junctions

KW - Cell motility

KW - HGF

KW - SMALL GTPASE RAC

KW - E-CADHERIN

KW - P21-ACTIVATED KINASE

KW - EPITHELIAL-CELLS

KW - PROSTATE-CANCER

KW - ALPHA-CATENIN

KW - BETA-CATENIN

KW - IQGAP1

KW - CDC42

KW - ACTIVATION

U2 - 10.1007/s00018-013-1528-5

DO - 10.1007/s00018-013-1528-5

M3 - Article

SN - 1420-682X

VL - 71

SP - 2759

EP - 2773

JO - Cellular and Molecular Life Sciences

JF - Cellular and Molecular Life Sciences

IS - 14

ER -