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Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation.


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.

SUBMITTER: Lim ST 

PROVIDER: S-EPMC2234035 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation.

Lim Ssang-Taek ST   Chen Xiao Lei XL   Lim Yangmi Y   Hanson Dan A DA   Vo Thanh-Trang TT   Howerton Kyle K   Larocque Nicholas N   Fisher Susan J SJ   Schlaepfer David D DD   Ilic Dusko D  

Molecular cell 20080101 1


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 loc  ...[more]

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