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

Academic Article

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. © 2008 Elsevier Inc. All rights reserved.
  • Authors

    Published In

  • Molecular Cell  Journal
  • Digital Object Identifier (doi)

    Author List

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

  • 9
  • End Page

  • 22
  • Volume

  • 29
  • Issue

  • 1