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(Journal Article) |
Molecular cell 29 (1): 9-22 (2008)
Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation.
Ssang-Taek Lim
,
Xiao Lei Chen
,
Yangmi Lim
,
Dan A Hanson
,
Thanh-Trang Vo
,
Kyle Howerton
,
Nicholas Larocque
,
Susan J Fisher
,
David D Schlaepfer
,
Dusko Ilic
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.