Under normal growth conditions, the tumor suppressor protein p53 is ubiquitinated and degraded, and cells proliferate. However, when cells are under stress, p53 accumulates and induces the expression of the gene encoding p21, which triggers cell cycle arrest. Signals from integrins, transmembrane receptors involved in cell adhesion, can counteract the activation of p53, but the mechanism involved is unclear. Lim et al. investigated whether focal adhesion kinase (FAK), a cytoplasmic tyrosine kinase stimulated by integrin activation, might regulate p53 activity. They generated fak–/– mice, which were embryonic lethal due to a block in mesodermal cell proliferation. Western blotting analyses showed that the abundance of p53 was higher in fak–/– embryos than in wild-type embryos. Whereas cells taken from fak–/– embryos did not proliferate in culture, those taken from fak–/–p53–/– or fak–/–p21–/– embryos did. Expression of FAK, a kinase-inactive FAK, or the FAK FERM domain (which regulates kinase activity) in fak–/–p21–/– fibroblasts reduced the abundance of p53 compared to that in control fak–/–p21–/– fibroblasts. The effects of FAK and FAK FERM were blocked by a proteasomal inhibitor. Immunofluorescence and Western blotting studies demonstrated that FAK was localized to the nucleus (an effect dependent on FERM) and that it mediated the ubiquitination and degradation of p53. Coimmunoprecipitation studies showed the formation of a complex between FAK, p53, and the E3 ubiquitin ligase Mdm2, which was also FERM-dependent. Depletion of FAK from human fibroblasts resulted in increased abundance of p53 and p21 and an increased susceptibility to cisplatin-induced apoptosis. Together, these data suggest a kinase-independent, FERM-dependent role for FAK as a nuclear scaffold protein that targets p53 for degradation and enhances cell proliferation.
S.-T. Lim, X. L. Chen, Y. Lim, D. A. Hanson, T.-T. Vo, K. Howerton, N. Larocque, S. J. Fisher, D. D. Schlaepfer, D. Ilic, Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol. Cell 29, 9-22 (2008). [PubMed]