Abstract
Focal adhesion kinase (FAK) plays an important role in signal transduction pathways initiated at sites of integrin-mediated cell adhesion to the extracellular matrix. Thus, FAK is involved in many aspects of the metastatic process including adhesion, migration and invasion. Recently, several small molecule inhibitors which target FAK catalytic activity have been developed by pharmaceutical companies. The current study was aimed at addressing whether inhibiting FAK targeting to focal adhesions (FA) represents an efficient alternative strategy to inhibit FAK downstream pathways. Using a mutagenesis approach to alter the targeting domain of FAK, we constructed a FAK mutant that fails to bind paxillin. Inhibiting FAK-paxillin interactions led to a complete loss of FAK localization at FAs together with reduced phosphorylation of FAK and FAK targets such as paxillin and p130Cas. This in turn resulted in altered FA dynamics and inhibition of cell adhesion, migration and invasion. Moreover, the migration properties of cells expressing the FAK mutant were reduced as compared to FAK-/- cells. This was correlated with a decrease in both phospho-Src and phospho-p130Cas levels at FAs. We conclude that targeting FAK-paxillin interactions is an efficient strategy to reduce FAK signalling and thus may represent a target for the development of new FAK inhibitors.
Highlights
IntroductionProgression of the disease results predominantly from the formation of metastases
In many cancers, progression of the disease results predominantly from the formation of metastases
While focal adhesions (FA) were clearly identified in both cell lines by paxillin staining, the Focal adhesion kinase (FAK) mutant is localized into the cytoplasm and not at FAs as shown by the absence of merged signals of FAK with paxillin (Figure 1C)
Summary
Progression of the disease results predominantly from the formation of metastases. Numerous reports have described overexpression, hyperphosphorylation and/or elevated activity of FAK in a variety of human cancers, including sarcomas, astrocytomas and carcinomas of the breast, colon, thyroid, prostate, oral cavity, liver, stomach and ovary [1]. These observations highlight a possible key role of FAK in tumourigenesis. The first experimental proof implicating FAK in tumour formation and progression was obtained by using conditional knock-out mice with selective fak deletion in the epidermis [2] This proof of concept experiment served as the cornerstone for the development of strategies aimed at inhibiting FAK activity using small-interfering RNAs [3] or small molecule inhibitors. This has been successfully achieved using a small molecule that targets the binding site of FAK and VEGFR3, resulting in suppressed breast cancer growth in vivo in mouse models [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
