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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    ABSTRACT: Cell-to-extracellular matrix adhesion is regulated by a multitude of pathways initiated distally to the core cell-matrix adhesion machinery, such as via growth factor signaling. In contrast to these extrinsically sourced pathways, we now identify a regulatory pathway that is intrinsic to the core adhesion machinery, providing an internal regulatory feedback loop to fine tune adhesion levels. This autoinhibitory negative feedback loop is initiated by cell adhesion to vitronectin, leading to PAK4 activation, which in turn limits total cell-vitronectin adhesion strength. Specifically, we show that PAK4 is activated by cell attachment to vitronectin as mediated by PAK4 binding partner integrin αvβ5, and that active PAK4 induces accelerated integrin αvβ5 turnover within adhesion complexes. Accelerated integrin turnover is associated with additional PAK4-mediated effects, including inhibited integrin αvβ5 clustering, reduced integrin to F-actin connectivity and perturbed adhesion complex maturation. These specific outcomes are ultimately associated with reduced cell adhesion strength and increased cell motility. We thus demonstrate a novel mechanism deployed by cells to tune cell adhesion levels through the autoinhibitory regulation of integrin adhesion.
    Molecular biology of the cell 10/2010; 21(19):3317-29. DOI:10.1091/mbc.E10-03-0245 · 4.47 Impact Factor
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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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    ABSTRACT: Comparative genomic hybridization (CGH) studies have provided a wealth of information on common copy number aberrations in pancreatic cancer, but the genes affected by these aberrations are largely unknown. To identify putative amplification target genes in pancreatic cancer, we performed a parallel copy number and expression survey in 13 pancreatic cancer cell lines using a 12,232-clone cDNA microarray, providing an average resolution of 300 kb throughout the human genome. CGH on cDNA microarray allowed highly accurate mapping of copy number increases and resulted in identification of 24 independent amplicons, ranging in size from 130 kb to 11 Mb. Statistical evaluation of gene copy number and expression data across all 13 cell lines revealed a set of 105 genes whose elevated expression levels were directly attributable to increased copy number. These included genes previously reported to be amplified in cancer as well as several novel targets for copy number alterations, such as p21-activated kinase 4 (PAK4), which was previously shown to be involved in cell migration, cell adhesion, and anchorage-independent growth. In conclusion, our results implicate a set of 105 genes that is likely to be actively involved in the development and progression of pancreatic cancer.
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