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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-013-1528-5) contains supplementary material, which is available to authorized users.

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

“…To investigate how PAK6 targets to cell-cell adhesions, we first confirmed that we could observe PAK6 at E-cadherin-rich cell-cell contacts as previously reported (Fram et al, 2014). Using lentiviral infection, we generated stable DU145 prostate cancer cell lines expressing GFP or GFP-PAK6.…”

“…Until recently, little was known about the basic cellular role of PAK6 other than its interaction with and phosphorylation of androgen receptor (Yang et al, 2001;Jaffer and Chernoff, 2002;Schrantz et al, 2004;Liu et al, 2013). However, last year, PAK6 was shown to localize to cell-cell adhesions in DU145 prostate cancer cells (Fram et al, 2014). The mechanism of targeting and its isoform specificity were not explored, but PAK6 was shown to promote the disassembly of cell-cell adhesions (Fram et al, 2014), a crucial step in epithelial-to-mesenchymal transition, one of the hallmarks of cancer.…”

“…However, last year, PAK6 was shown to localize to cell-cell adhesions in DU145 prostate cancer cells (Fram et al, 2014). The mechanism of targeting and its isoform specificity were not explored, but PAK6 was shown to promote the disassembly of cell-cell adhesions (Fram et al, 2014), a crucial step in epithelial-to-mesenchymal transition, one of the hallmarks of cancer.…”

PAK5 mediates cell: cell adhesion integrity via interaction with E-cadherin in bladder cancer cells

“…One of the studies has demonstrated that Cdc42 regulates the apical junction formation in human bronchial epithelial cells through PAK4 32 . PAK6, which was initially identified to be an androgen receptor protein, and has recently be reported to be involved in cell: cell dissociation in response to HGF, independent of androgen receptor (AR) signalling 33 and is thought to drive colony escape 34 .…”

“…Mechanistically, a complex of PAK6/E-cadherin/IQGAP1 was identified as the cells dissociate in response to HGF 35 . Group 2 member PAK5 has been shown to interact with p120-Catenin, an important component of the cadherin-catenin-complex at adherens junctions 36 .…”