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

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.

Pubmed ID: 18206965

Authors

  • Lim ST
  • Chen XL
  • Lim Y
  • Hanson DA
  • Vo TT
  • Howerton K
  • Larocque N
  • Fisher SJ
  • Schlaepfer DD
  • Ilic D

Journal

Molecular cell

Publication Data

January 18, 2008

Associated Grants

  • Agency: NCRR NIH HHS, Id: C06RR16490
  • Agency: NCI NIH HHS, Id: CA102310
  • Agency: NCI NIH HHS, Id: CA75240
  • Agency: NCI NIH HHS, Id: CA87038
  • Agency: NCI NIH HHS, Id: CA87652
  • Agency: NCI NIH HHS, Id: R01 CA075240
  • Agency: NCI NIH HHS, Id: R01 CA075240-11
  • Agency: NCI NIH HHS, Id: R01 CA087038
  • Agency: NCI NIH HHS, Id: R01 CA087038-05
  • Agency: NCI NIH HHS, Id: R01 CA102310
  • Agency: NCI NIH HHS, Id: R01 CA102310-05

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Cell Division
  • Cell Nucleus
  • Cell Survival
  • Cisplatin
  • Cyclin-Dependent Kinase Inhibitor p21
  • Embryonic Development
  • Fibroblasts
  • Focal Adhesion Kinase 1
  • Mesoderm
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Proteasome Endopeptidase Complex
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Staurosporine
  • Tumor Suppressor Protein p53
  • Ubiquitin
  • Ubiquitination