P21-activated kinase 4 interacts with integrin alpha v beta 5 and regulates alpha v beta 5-mediated cell migration

Karolinska Institutet, Department of Microbiology, Pathology, and Immunology, SE-141 86 Huddinge, Sweden.
The Journal of Cell Biology (Impact Factor: 9.83). 10/2002; 158(7):1287-97.
Source: PubMed


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 beta 5 subunit, an association that was also found in mammalian cells between endogenous PAK4 and integrin alpha v beta 5. Furthermore, we mapped the PAK4 binding to the membrane-proximal region of integrin beta 5, and identified an integrin-binding domain at aa 505-530 in the COOH terminus of PAK4. Importantly, engagement of integrin alpha v beta 5 by cell attachment to vitronectin led to a redistribution of PAK4 from the cytosol to dynamic lamellipodial structures where PAK4 colocalized with integrin alpha v beta 5. Functionally, PAK4 induced integrin alpha v beta 5-mediated, but not beta1-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 alpha v beta 5 and selectively promotes integrin alpha v beta 5-mediated cell migration.

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Available from: Zhilun Li, Feb 27, 2014
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    • "Inhibition by PAK4 of these transient CMAC-precursor interactions may also explain the reduced frequency of small, nascent CMACs observed with PAK4 overexpression. In addition to these results, a direct effect of PAK4 on integrin clustering and function is also supported by our earlier identification of a direct interaction between integrin ␤5 and PAK4 (Zhang et al., 2002) and even more so by our recent findings that PAK4 directly phosphorylates the ␤5 cytoplasmic tail at two serine residues, the mutation of which blocks PAK4-induced cell migration (Li et al., 2010). "
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    • "Both subgroup kinases are involved in the regulation of MAP kinase cascades, cell cycle, and apoptosis (for review, see Bokoch, 2003; Jaffer and Chernoff, 2002), and were shown to regulate cell cytoskeletal changes. Individual PAKs act through a number of targets including the myosin light chain kinase (MLCK) (Sanders et al., 1999), regulatory myosin light chain (Goeckeler et al., 2000), Caldesmon (Foster et al., 2000), filamin (Vadlamudi et al., 2002), desmin (Ohtakara et al., 2000), Lim kinase (Dan et al., 2001; Edwards et al., 1999), and integrin alpha v beta 5 (Zhang et al., 2002). Subgroup I and II PAKs may carry out different functions in a same cell as highlighted in Schneeberger and Raabe (2003). "
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