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 Sears, Alan R. Clarke, Margaret C. Frame, Owen J. Sansom

Research output: Contribution to journalArticle

115 Citations (Scopus)

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

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Focal Adhesion Protein-Tyrosine Kinases
Regeneration
Carcinogenesis
DNA Damage
Intestinal Mucosa
DNA
Tumor Suppressor Proteins
Integrins
Protein Kinases
Colorectal Neoplasms
Homeostasis
Chemical activation
Wounds and Injuries
Proteins

Keywords

  • Cellcycle
  • Humdisease

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Ashton, G. H., Morton, J. P., Myant, K., Phesse, T. J., Ridgway, R. A., Marsh, V., ... 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

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 J.; Ridgway, Rachel A.; Marsh, Victoria; Wilkins, Julie A.; Athineos, Dimitris; Muncan, Vanesa; Kemp, Richard; Neufeld, Kristi; Clevers, Hans; Brunton, Valerie; Winton, Douglas J.; Wang, Xiaoyan; Sears, Rosalie; Clarke, Alan R.; Frame, Margaret C.; Sansom, Owen J.

In: Developmental Cell, Vol. 19, No. 2, 08.2010, p. 259-269.

Research output: Contribution to journalArticle

Ashton, GH, Morton, JP, Myant, K, Phesse, TJ, Ridgway, RA, Marsh, V, Wilkins, JA, Athineos, D, Muncan, V, Kemp, R, Neufeld, K, Clevers, H, Brunton, V, Winton, DJ, Wang, X, Sears, R, Clarke, AR, Frame, MC & Sansom, OJ 2010, 'Focal Adhesion Kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling', Developmental Cell, vol. 19, no. 2, pp. 259-269. https://doi.org/10.1016/j.devcel.2010.07.015
Ashton, Gabrielle H. ; Morton, Jennifer P. ; Myant, Kevin ; Phesse, Toby J. ; Ridgway, Rachel A. ; Marsh, Victoria ; Wilkins, Julie A. ; Athineos, Dimitris ; Muncan, Vanesa ; Kemp, Richard ; Neufeld, Kristi ; Clevers, Hans ; Brunton, Valerie ; Winton, Douglas J. ; Wang, Xiaoyan ; Sears, Rosalie ; Clarke, Alan R. ; Frame, Margaret C. ; Sansom, Owen J. / Focal Adhesion Kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling. In: Developmental Cell. 2010 ; Vol. 19, No. 2. pp. 259-269.
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