Abstract
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.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Apoptosis / drug effects
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Cell Division / physiology
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Cell Nucleus / metabolism
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Cell Survival / physiology
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Cisplatin / pharmacology
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Cyclin-Dependent Kinase Inhibitor p21 / deficiency
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / physiology
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Embryonic Development / genetics
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Embryonic Development / physiology
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Focal Adhesion Kinase 1 / chemistry
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Focal Adhesion Kinase 1 / deficiency
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Focal Adhesion Kinase 1 / genetics
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Focal Adhesion Kinase 1 / physiology*
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Mesoderm / pathology
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Mice
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Mice, Knockout
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Molecular Sequence Data
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Proteasome Endopeptidase Complex / metabolism
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Protein Structure, Tertiary
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Sequence Alignment
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Sequence Homology, Amino Acid
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Staurosporine / pharmacology
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Tumor Suppressor Protein p53 / metabolism*
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Ubiquitin / metabolism
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Ubiquitination
Substances
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CDKN1A protein, human
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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Tumor Suppressor Protein p53
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Ubiquitin
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Focal Adhesion Kinase 1
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PTK2 protein, human
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Ptk2 protein, mouse
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Proteasome Endopeptidase Complex
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Staurosporine
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Cisplatin