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Control of adhesion-dependent cell survival by focal adhesion kinase
S M Frisch1, K Vuori, E Ruoslahti
1Burnham Institute, La Jolla Cancer Research Center, California 92037, USA. sfrisch@ljcrf.edu
Abstract:
The interactions of integrins with extracellular matrix proteins can activate focal adhesion kinase (FAK) and suppress apoptosis in normal epithelial and endothelial cells; this subset of apoptosis has been termed "anoikis." Here, we demonstrate that FAK plays a role in the suppression of anoikis. Constitutively activated forms of FAK rescued two established epithelial cell lines from anoikis. Both the major autophosphorylation site (Y397) and a site critical to the kinase activity (K454) of FAK were required for this effect. Activated FAK also transformed MDCK cells, by the criteria of anchorage-independent growth and tumor formation in nude mice. We provide evidence that this transformation resulted primarily from the cells' resistance to anoikis rather than from the activation of growth factor response pathways. These results indicate that FAK can regulate anoikis and that the conferral of anoikis resistance may suffice to transform certain epithelial cells.
Insights
Focal adhesion kinase (FAK) prevents anoikis, a form of apoptosis, in normal cells. Activated FAK also transforms epithelial cells by conferring resistance to anoikis, indicating FAK
Area of Science:
- Cell biology
- Molecular biology
- Cancer research
Background:
- Integrin interactions with extracellular matrix proteins activate focal adhesion kinase (FAK).
- FAK activation normally suppresses anoikis, a form of apoptosis, in epithelial and endothelial cells.
Purpose of the Study:
- To investigate the role of FAK in the suppression of anoikis.
- To determine if FAK-mediated anoikis resistance can transform epithelial cells.
Main Methods:
- Utilized constitutively activated forms of FAK in epithelial cell lines.
- Assessed anoikis suppression by FAK activation.
- Evaluated anchorage-independent growth and tumor formation in nude mice for FAK-transformed cells.
Main Results:
- Constitutively activated FAK rescued epithelial cells from anoikis.
- Specific sites on FAK (Y397 and K454) were essential for anoikis suppression.
- Activated FAK transformed MDCK cells, primarily through anoikis resistance, not growth factor pathways.
Conclusions:
- FAK plays a critical role in regulating anoikis.
- Conferring resistance to anoikis via FAK activation is sufficient to transform certain epithelial cells, suggesting FAK as a potential therapeutic target in cancer.