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.
Mesh Terms:
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
Mol. Cell
Date: Jan. 18, 2008
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