p21-activated kinase 4 interacts with integrin αvβ5 and regulates αvβ5-mediated cell migration

Abstract

p21-activated kinase 1 (PAK1) can affect cell migration (Price et al., 1998; del Pozo et al., 2000) and modulate myosin light chain kinase and LIM kinase, which are components of the cellular motility machinery (Edwards, D.C., L.C. Sanders, G.M. Bokoch, and G.N. Gill. 1999. Nature Cell Biol. 1:253–259; Sanders, L.C., F. Matsumura, G.M. Bokoch, and P. de Lanerolle. 1999. Science. 283:2083–2085). We here present a novel cell motility pathway by demonstrating that PAK4 directly interacts with an integrin intracellular domain and regulates carcinoma cell motility in an integrin-specific manner. Yeast two-hybrid screening identified PAK4 binding to the cytoplasmic domain of the integrin β5 subunit, an association that was also found in mammalian cells between endogenous PAK4 and integrin αvβ5. Furthermore, we mapped the PAK4 binding to the membrane-proximal region of integrin β5, and identified an integrin-binding domain at aa 505–530 in the COOH terminus of PAK4. Importantly, engagement of integrin αvβ5 by cell attachment to vitronectin led to a redistribution of PAK4 from the cytosol to dynamic lamellipodial structures where PAK4 colocalized with integrin αvβ5. Functionally, PAK4 induced integrin αvβ5–mediated, but not β1-mediated, human breast carcinoma cell migration, while no changes in integrin cell surface expression levels were observed. In conclusion, our results demonstrate that PAK4 interacts with integrin αvβ5 and selectively promotes integrin αvβ5–mediated cell migration.

P21‐activated kinase 5 is overexpressed during colorectal cancer progression and regulates colorectal carcinoma cell adhesion and migration

“…4f). These data are in agreement with our previous finding that PAK4 regulates breast cancer cell adhesion and migration on vitronectin, 11 indicating that PAK5 regulates integrin-mediated cell adhesion and migration in CRC cells.…”

“…30,31 This process is major regulated by integrin and small GTPase Cdc42, and Rac1 whose targets are PAK family. [32][33][34][35] In our previous study, we found that PAK4 regulate integrin avb5-mediated breast carcinoma cell migration, 11 indicating that the Group B PAKs might be important to cell motility. Overexpression of PAK5 promoted formation of filopodia and neurite extension in N1E-115 cells.…”

“…9,10 Our previous study demonstrated that PAK4 regulated integrin avb5-mediated breast carcinoma cell migration. 11 Different PAK family members have different tissue-specific expression patterns. PAK4 was found to be overexpressed in 78% of a variety of human cancer cell lines, 12 whereas PAK5 and PAK6 showed restricted tissue-specific expression patterns that both were found to be highly expressed in the brain.…”

A βPix–Pak2a signaling pathway regulates cerebral vascular stability in zebrafish

“…In further support, Pak family proteins have been implicated in integrin signaling. Upon integrin ␣ v ␤ 5 binding to vitronectin, Pak4 becomes colocalized with this integrin (37). Therefore, reduction or loss of ␤Pix expression might result in disruption to the paxillin/GIT/Pix/Pak complex at focal adhesions and therefore to a reduction in integrin signaling and adhesion.…”

Recombinant CD44-HABD is a novel and potent direct angiogenesis inhibitor enforcing endothelial cell-specific growth inhibition independently of hyaluronic acid binding

“…Migration assays were performed in Transwell migration chambers (pore size 8 mm; Costar, London, UK) essentially as described (Zhang et al, 2002). The lower compartment of the chambers contained 1 mg/ml high molecular weight HA (Sigma).…”