Focal adhesion kinase (FAK) is upregulated in several epithelial tumours and there has been considerable interest in developing small molecule kinase inhibitors of FAK. However, FAK also has important adaptor functions within the cell, integrating signals from both integrins and growth factors. To investigate the role of FAKs kinase domain, we generated fakdeficient squamous cell carcinoma (SCC) cell lines. Re-expression of a wild type or kinase dead FAK allowed us to delineate its kinase dependent functions. In addition, we used the novel FAK kinase inhibitor PF-562,271. The kinase activity of FAK was important for tumour cell migration and polarity but more striking was its requirement for the anchorage independent 3 dimensional (3D) proliferation of SCC cells and their growth as xenografts in mice. Inhibition of FAK activity and prevention of growth in 3D correlated with Src inhibition. We further identified a mechanism whereby FAK regulates proliferation in 3D via regulation of the kinase activity of Src. This was dependent on the kinase activity of FAK and its resulting phosphorylation on Y397 that provides a high affinity binding site for Src. These data support the further development of FAK kinase inhibitors as agents that have the potential to inhibit both tumour cell migration and proliferation.Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase found at focal adhesions, which are sites of integrin clustering at the cell-extracellular matrix interface, where it provides both signalling and scaffolding functions. It is involved in the dynamic regulation of these adhesion sites, a process that is critical for the control of cell migration. 1,2 FAK is also important for tumour cell invasion and metastasis, 3 where it is believed to integrate growth factor and integrin signals to promote both tumour cell migration and invasion. 2-4 FAK has also been linked to the protection of cells from suspension-induced apoptosis or anoikis 5-8 and introduction of inhibitory FAK constructs into tumour cells can lead to cell detachment and apoptosis. 9 FAK is therefore involved in a number of processes that can impact on the malignant phenotype, the importance of which is not fully understood. In support however, of a direct role for FAK in tumourigenesis we have shown, using targeted deletion of fak in mouse skin, the absolute requirement for FAK in malignant tumour formation. 10 More recently deletion of FAK has also been shown to be required for mammary tumour progression and the androgen-independent formation of neuroendocrine carcinoma in a prostate mouse model. [11][12][13][14][15] FAK is over-expressed in a number of human epithelial tumours [16][17][18] and FAK has therefore emerged as a potential target for cancer therapy 18-20 with a number of FAK kinase inhibitors being developed, one of which PF-562,271 is currently in clinical development. 21 There has been some debate surrounding the development of such agents as in addition to having kinase activity the adaptor function of FAK plays a key role in...
Telavancin exhibited substantial antimicrobial activity against staphylococcal biofilms, including GISA strains. This study supports the case for the evaluation of telavancin in the treatment of staphylococcal biofilm-associated infections.
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that integrates signals downstream of integrin and growth factor activation. Previously, we have shown that skin-specific loss of fak prevents chemically induced skin carcinogenesis in mice following phorbol ester treatment. In this study, we show that skinspecific deletion of fak prevents mobilization of stem cells within the bulge region of the hair follicle, which are the precursors of papillomas following phorbol ester treatment. We also show that phorbol ester treatment results in activation of-catenin within the skin and that FAK is required for β-catenin-induced stem cell mobilization. In addition, inhibition of Src kinase activity, a major binding partner of FAK also prevents stem cell mobilization. We show that FAK is required for the nuclear localization of β-catenin in the skin following phorbol ester treatment and the transcriptional activation of the β-catenin target gene c-Myc. This provides the first evidence of cross-talk between integrin and Wnt signalling pathways in the control of epidermal stem cells and the early events associated with skin carcinogenesis.
Overexpression of matriptase has been reported in a variety of human cancers and is sufficient to trigger tumor formation in mice, but the importance of matriptase in breast cancer remains unclear. We analysed matriptase expression in 16 human breast cancer cell lines and in 107 primary breast tumors. The data revealed considerable diversity in the expression level of this protein indicating that the significance of matriptase may vary from case to case. Matriptase protein expression was correlated with HER2 expression and highest expression was seen in HER2-positive cell lines, indicating a potential role in this subgroup. Stable overexpression of matriptase in two breast cancer cell lines had different consequences. In MDA-MB-231 human breast carcinoma cells the only noted consequence of matriptase overexpression was modestly impaired growth in vivo. In contrast, overexpression of matriptase in 4T1 mouse breast carcinoma cells resulted in visible changes in morphology, actin staining and cell to cell contacts. This correlated with downregulation of the cell-cell adhesion molecule E-cadherin. These results suggest that the functions of matriptase in breast cancer are likely to be variable and cell context dependent.
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