Focal adhesion kinase (FAK) plays a critical role in controlling adhesion-dependent cell survival, particularly in suppressing anoikis, a form of apoptosis that occurs when cells lose contact with the extracellular matrix. This study demonstrates that constitutively activated FAK rescues epithelial cells from anoikis. The major autophosphorylation site (Y397) and a site critical to kinase activity (K454) of FAK are essential for this effect. FAK interacts with various proteins, including c-src, grb2, phosphatidylinositol-3-kinase, paxillin, and p130cas, and is involved in integrin signaling. The study shows that FAK can regulate anoikis and that resistance to anoikis may be sufficient to transform certain epithelial cells. Activated FAK also transformed MDCK cells, indicating that the resistance to anoikis, rather than growth factor pathways, is responsible for the transformation. The study further shows that CD2-FAK, a membrane-targeted form of FAK, is constitutively activated in MDCK cells and confers anoikis resistance. CD2-FAK also promotes anchorage-independent growth and tumorigenicity in MDCK cells. The results suggest that FAK contributes to epithelial carcinogenesis by controlling anoikis without affecting growth factor response pathways. The study highlights the importance of FAK in integrin-mediated cell survival and transformation.Focal adhesion kinase (FAK) plays a critical role in controlling adhesion-dependent cell survival, particularly in suppressing anoikis, a form of apoptosis that occurs when cells lose contact with the extracellular matrix. This study demonstrates that constitutively activated FAK rescues epithelial cells from anoikis. The major autophosphorylation site (Y397) and a site critical to kinase activity (K454) of FAK are essential for this effect. FAK interacts with various proteins, including c-src, grb2, phosphatidylinositol-3-kinase, paxillin, and p130cas, and is involved in integrin signaling. The study shows that FAK can regulate anoikis and that resistance to anoikis may be sufficient to transform certain epithelial cells. Activated FAK also transformed MDCK cells, indicating that the resistance to anoikis, rather than growth factor pathways, is responsible for the transformation. The study further shows that CD2-FAK, a membrane-targeted form of FAK, is constitutively activated in MDCK cells and confers anoikis resistance. CD2-FAK also promotes anchorage-independent growth and tumorigenicity in MDCK cells. The results suggest that FAK contributes to epithelial carcinogenesis by controlling anoikis without affecting growth factor response pathways. The study highlights the importance of FAK in integrin-mediated cell survival and transformation.