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

Ashton, Gabrielle H., Morton, Jennifer P., Myant, Kevin, Phesse, Toby, Ridgway, Rachel A., Marsh Durban, Victoria, Wilkins, Julie A., Athineos, Dimitris, Muncan, Vanesa, Kemp, Richard, Neufeld, Kristi, Clevers, Hans, Brunton, Valerie, Winton, Douglas J., Wang, Xiaoyan, Sears, Rosalie C., Clarke, Alan Richard, Frame, Margaret C. and Sansom, Owen J. 2010. Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling. Developmental Cell 19 (2) , pp. 259-269. 10.1016/j.devcel.2010.07.015

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords: cell cycle; Humdisease
Publisher: Elsevier
ISSN: 1534-5807
Last Modified: 04 Jun 2017 03:17
URI: http://orca.cf.ac.uk/id/eprint/19447

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