Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation.
FAK is known as an integrin- and growth factor-associated tyrosine kinase promoting cell motility. Here we show that, during mouse development, FAK inactivation results in p53- and p21-dependent mesodermal cell growth arrest. Reconstitution of primary FAK-/-p21-/- fibroblasts revealed that FAK, in a kinase-independent manner, facilitates p53 turnover via enhanced Mdm2-dependent p53 ubiquitination. p53 inactivation by FAK required FAK FERM F1 lobe binding to p53, FERM F2 lobe-mediated nuclear localization, and FERM F3 lobe for connections to Mdm2 and proteasomal degradation. Staurosporine or loss of cell adhesion enhanced FERM-dependent FAK nuclear accumulation. In primary human cells, FAK knockdown raised p53-p21 levels and slowed cell proliferation but did not cause apoptosis. Notably, FAK knockdown plus cisplatin triggered p53-dependent cell apoptosis, which was rescued by either full-length FAK or FAK FERM re-expression. These studies define a scaffolding role for nuclear FAK in facilitating cell survival through enhanced p53 degradation under conditions of cellular stress.
Pubmed ID: 18206965 RIS Download
Amino Acid Sequence | Animals | Apoptosis | Cell Division | Cell Nucleus | Cell Survival | Cisplatin | Cyclin-Dependent Kinase Inhibitor p21 | Embryonic Development | Fibroblasts | Focal Adhesion Kinase 1 | Mesoderm | Mice | Mice, Knockout | Molecular Sequence Data | Proteasome Endopeptidase Complex | Protein Structure, Tertiary | Sequence Alignment | Sequence Homology, Amino Acid | Staurosporine | Tumor Suppressor Protein p53 | Ubiquitin | Ubiquitination