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

Ashton, G. H. and Morton, J. P. and Myant, K. and Phesse, T. J. and Ridgway, R.A. and Marsh, V. and Wilkins, J. A. and Athineos, D. and Muncan, V. and Kemp, R. and Neufeld, K. and Clevers, H. and Brunton, V. and Winton, D. J. and Wang, X. and Sears, R. and Clarke, A.R. and Frame, M. C. and Sansom, O.J. (2010) Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling. Developmental Cell, 19, 259-69. ISSN 1534-5807.

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Official URL: http://dx.doi.org/10.1016/j.devcel.2010.07.015

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
Institutes:Hubrecht Instituut
ID Code:9487
Deposited On:04 Jan 2011 01:00
Last Modified:07 Sep 2011 17:01

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