Nuclear FAK Promotes Cell Proliferation and Survival through FERM-Enhanced p53 Degradation

• Published in: Molecular cell Vol. 29; no. 1; pp. 9 - 22
• Main Authors: Lim, Ssang-Taek, Chen, Xiao Lei, Lim, Yangmi, Hanson, Dan A., Vo, Thanh-Trang, Howerton, Kyle, Larocque, Nicholas, Fisher, Susan J., Schlaepfer, David D., Ilic, Dusko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18-01-2008
• Subjects: Amino Acid Sequence; Animals; Apoptosis - drug effects; Cell Division - physiology; Cell Nucleus - metabolism; Cell Survival - physiology; CELLCYCLE; Cisplatin - pharmacology; Cyclin-Dependent Kinase Inhibitor p21 - deficiency; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - physiology; Embryonic Development - genetics; Embryonic Development - physiology; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Focal Adhesion Kinase 1 - chemistry; Focal Adhesion Kinase 1 - deficiency; Focal Adhesion Kinase 1 - genetics; Focal Adhesion Kinase 1 - physiology; Mesoderm - pathology; Mice; Mice, Knockout; Molecular Sequence Data; Proteasome Endopeptidase Complex - metabolism; Protein Structure, Tertiary; Sequence Alignment; Sequence Homology, Amino Acid; SIGNALING; Staurosporine - pharmacology; Tumor Suppressor Protein p53 - metabolism; Ubiquitin - metabolism; Ubiquitination; CELLCYCLE; SIGNALING
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2007.11.031

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.