Focal Adhesion Kinase: A regulator of focal adhesion dynamics and cell movement

Department of Microbiology, Health Science Center, University of Virginia, Charlottesville, Virginia, VA 22908, USA.
Oncogene (Impact Factor: 8.46). 12/2000; 19(49):5606-13. DOI: 10.1038/sj.onc.1203877
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Engagement of integrin receptors with extracellular ligands gives rise to the formation of complex multiprotein structures that link the ECM to the cytoplasmic actin cytoskeleton. These adhesive complexes are dynamic, often heterogeneous structures, varying in size and organization. In motile cells, sites of adhesion within filopodia and lamellipodia are relatively small and transient and are referred to as 'focal complexes,' whereas adhesions underlying the body of the cell and localized to the ends of actin stress fibers are referred to as 'focal adhesions'. Signal transduction through focal complexes and focal adhesions has been implicated in the regulation of a number of key cellular processes, including growth factor induced mitogenic signals, cell survival and cell locomotion. The formation and remodeling of focal contacts is a dynamic process under the regulation of protein tyrosine kinases and small GTPases of the Rho family. In this review, we consider the role of the focal complex associated protein tyrosine kinase, Focal Adhesion Kinase (FAK), in the regulation of cell movement with the emphasis on how FAK regulates the flow of signals from the ECM to the actin cytoskeleton.

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    • "In addition, recruitment of Focal adhesion kinase (FAK)/Src complex mediates and regulates the signaling events downstream of integrin-dependent pathway [27]. The cytoplasmic protein tyrosine kinase, FAK, is involved in integrin-mediated signal transduction and plays an important role in the control of cell spreading, migration, and survival [83]. Src/FAK mutually regulates the activity of each other and promotes normal and cancer cell migration by regulating focal adhesion formation and turnover through multiple signaling connections [41]. "
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    ABSTRACT: Pancreatic ductal adenocarcinoma is characterized by extensive local tumor invasion, metastasis and early systemic dissemination. The vast majority of pancreatic cancer (PaCa) patients already have metastatic complications at the time of diagnosis, and the death rate of this lethal type of cancer has increased over the past decades. Thus, efforts at identifying novel molecularly targeted therapies are priorities. Recent studies have suggested that serotonin (5-HT) contributes to the tumor growth in a variety of cancers including prostate, colon, bladder and liver cancer. However, there is lack of evidence about the impact of 5-HT receptors on promoting pancreatic cancer. Having considered the role of 5-HT-1 receptors, especially 5-HT1B and 5-HT1D subtypes in different types of malignancies, the aim of this study was to investigate the role of 5-HT1B and 5-HT1D receptors in PaCa growth and progression and analyze their potential as cytotoxic targets. We found that knockdown of 5-HT1B and 5-HT1D receptors expression, using specific small interfering RNA (siRNA), induced significant inhibition of proliferation and clonogenicity of PaCa cells. Also, it significantly suppressed PaCa cells invasion and reduced the activity of uPAR/MMP-2 signaling and Integrin/Src/Fak-mediated signaling, as integral tumor cell pathways associated with invasion, migration, adhesion, and proliferation. Moreover, targeting 5-HT1B and 5-HT1D receptors down-regulates zinc finger ZEB1 and Snail proteins, the hallmarks transcription factors regulating epithelial-mesenchymal transition (EMT), concomitantly with up-regulating of claudin-1 and E-Cadherin. In conclusion, our data suggests that 5-HT1B- and 5-HT1D-mediated signaling play an important role in the regulation of the proliferative and invasive phenotype of PaCa. It also highlights the therapeutic potential of targeting of 5-HT1B/1D receptors in the treatment of PaCa, and opens a new avenue for biomarkers identification, and valuable new therapeutic targets for managing pancreatic cancer.
    PLoS ONE 08/2014; 9(8):e105245. DOI:10.1371/journal.pone.0105245 · 3.23 Impact Factor
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    • "Aside from phosphorylation inhibition and the potential interaction with integrin αV, FAK is involved in the integrin-dependent activation of phosphoinositide 3-kinases (PI3Ks). PI3K inhibitors suppress FAK-promoted cell migration in a concentrationdependent manner (Cohen and Guan, 2005; Parsons et al., 2000). The Akt cascade can be activated by receptor tyrosine kinases, integrins, G-protein-coupled receptors and PI3K (Carnero et al., 2008). "
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    ABSTRACT: Furanodiene is a bioactive compound isolated from Curcuma wenyujin Y. H. Chen et C. Ling (C. wenyujin). It is one of the major components of volatile oil extracted from C. wenyujin. Furanodiene has anti-tumor activities in various cancer cell lines, as well as anti-metastatic activities. However, the underlying mechanisms of anti-metastatic activities of furanodiene have not been well investigated. In this study, we demonstrated that at low concentrations (5-25μM), furanodiene inhibited adhesion, migration and invasion of breast cancer cells, but it did not induce cytotoxicity, apoptosis and cell cycle arrest. Furthermore, the underlying mechanisms for the anti-metastatic activity of furanodinene were also investigated. Furanodiene down-regulated the integrin αV expression, β-catenin expression, focal adhesion kinase (FAK) phosphorylation, Akt phosphorylation, and PI3 kinase p85 phosphorylation, and all of these were involved in modulation of the tumor metastasis process. In addition, an interference of metastasis was also observed in MDA-MB-231 cells through the regulation of the matrix metalloproteinase 9 (MMP-9) releases. Our results suggested that furanodiene might be the primary contributor to the anti-cancer effects of volatile oil extracts, and it might be a good therapeutic target for highly metastatic breast cancer.
    European journal of pharmacology 05/2014; 737. DOI:10.1016/j.ejphar.2014.04.043 · 2.53 Impact Factor
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    • "Before beginning to grow or differentiate, anchoragedependent cells have to spread on the extracellular matrix (ECM), a process mediated by a set of cell-adhesion proteins that associate with numerous cytoskeletal and signaling proteins to form focal adhesions (FAs) (Parsons et al., 2000; Gaus et al., 2006). Integrin plays important role in cell spreading (Bhadriraju and Hansen, 2002; Ekblom et al., 2003), its binding to the ECM, followed by its clustering, inducing autophosphorylation of the focal adhesion kinase (FAK), which is one of the major kinases found in FAs implicated in the FA signaling (Wei et al., 1999; Weisner et al., 2005; Goetz et al., 2008). "
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    ABSTRACT: We have investigated the relationship between the spreading of anchorage-dependent cells and the surface-density distribution of plasma membrane adhesion proteins. The surface positioning and density of integrin β1, caveolin-1 (cav-1), the phosphorylated caveolin-1 (p-cav-1) and the focal adhesion kinase (FAK) located on the adhering cell membrane (ACM) of HUVEC cells was studied. Imaging with TIRF microscopy was used, which enabled us to observe a few-nanometers-thin section of the cell above the plasma membrane in combination with image-based analyses. Integrin β1 and cav-1 have spatial interdependence on the ACM. Cells treated with substances that act on cell spreading caused changes in the size of the ACM area, as well as a redistribution of several proteins under investigation. Changes to the ACM area correlated positively with those to the surface density of the cav-1. The high integrin β1 and the low cav-1 surface density, and vice versa, following the treatments show that the presence of one of them not only spatially excludes, but also reduces, the occurrence of the other protein on the ACM, which indicates a regulative mechanism between integrin β1 and cav-1.
    Cell Biology International 12/2013; 37(12). DOI:10.1002/cbin.10155 · 1.93 Impact Factor
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