Control of adhesion-dependent cell survival by focal adhesion kinase.
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.
Frisch
S M
SM
Burnham Institute, La Jolla Cancer Research Center, California 92037, USA. sfrisch@ljcrf.edu
Vuori
K
K
Ruoslahti
E
E
Chan-Hui
P Y
PY
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D018801:CD2 Antigens / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004285:Dogs; D004789:Enzyme Activation; D004847:Epithelial Cells; D005347:Fibroblasts; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D007668:Kidney; D051379:Mice; D008819:Mice, Nude; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D018801:CD2 Antigens; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D051419:Paxillin; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C496062:Pxn protein, mouse; C496063:Pxn protein, rat; D011993:Recombinant Fusion Proteins; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; C496052:Ptk2 protein, rat; D017871:Calcium-Calmodulin-Dependent Protein Kinases