Focal Adhesion Kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling

Gabrielle H. Ashton, Jennifer P. Morton, Kevin Myant, Toby J. Phesse, Rachel A. Ridgway, Victoria Marsh, Julie A. Wilkins, Dimitris Athineos, Vanesa Muncan, Richard Kemp, Kristi Neufeld, Hans Clevers, Valerie Brunton, Douglas J. Winton, Xiaoyan Wang, Rosalie C. Sears, Alan R. Clarke, Margaret C. Frame, Owen J. Sansom

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

The intestinal epithelium has a remarkable capacity to regenerate after injury and DNA damage. Here, we show that the integrin effector protein Focal Adhesion Kinase (FAK) is dispensable for normal intestinal homeostasis and DNA damage signaling, but is essential for intestinal regeneration following DNA damage. Given Wnt/c-Myc signaling is activated following intestinal regeneration, we investigated the functional importance of FAK following deletion of the Apc tumor suppressor protein within the intestinal epithelium. Following Apc loss, FAK expression increased in a c-Myc-dependent manner. Codeletion of Apc and Fak strongly reduced proliferation normally induced following Apc loss, and this was associated with reduced levels of phospho-Akt and suppression of intestinal tumorigenesis in Apc heterozygous mice. Thus, FAK is required downstream of Wnt Signaling, for Akt/mTOR activation, intestinal regeneration, and tumorigenesis. Importantly, this work suggests that FAK inhibitors may suppress tumorigenesis in patients at high risk of developing colorectal cancer.

Original languageEnglish (US)
Pages (from-to)259-269
Number of pages11
JournalDevelopmental Cell
Volume19
Issue number2
DOIs
StatePublished - Aug 2010

Keywords

  • Cellcycle
  • Humdisease

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Focal Adhesion Kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling'. Together they form a unique fingerprint.

  • Cite this

    Ashton, G. H., Morton, J. P., Myant, K., Phesse, T. J., Ridgway, R. A., Marsh, V., Wilkins, J. A., Athineos, D., Muncan, V., Kemp, R., Neufeld, K., Clevers, H., Brunton, V., Winton, D. J., Wang, X., Sears, R. C., Clarke, A. R., Frame, M. C., & Sansom, O. J. (2010). Focal Adhesion Kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling. Developmental Cell, 19(2), 259-269. https://doi.org/10.1016/j.devcel.2010.07.015