Editors' ChoiceCancer

As a Matter of Fak…

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Science Signaling  31 Aug 2010:
Vol. 3, Issue 137, pp. ec262
DOI: 10.1126/scisignal.3137ec262

Focal adhesion kinase (Fak) transduces integrin-mediated survival signaling, and its abundance is increased in various tumors, including colorectal cancer. Loss of adenomatous polyposis coli (APC), a scaffold protein that promotes the degradation of the Wnt effector β-catenin, is associated with colorectal cancers, and Wnt signaling is activated during intestinal regeneration following genetic or mechanical insult. Intestinal stem cells have been implicated in colorectal tumorigenesis and are required for homeostasis and regeneration of the intestinal epithelium. Ashton et al. report that Fak was present in normal mouse intestinal epithelium, and its abundance increased after removal of Apc from the intestinal epithelium and during regeneration following irradiation. Fak was required for regeneration but not for homeostatic replacement of intestinal epithelial cells lost to normal turnover. Fak was also required for activation of signaling through the mammalian target of rapamycin (mTOR) pathway in regenerating epithelia, as indicated by an increase of phosphorylated forms of Akt and mTOR (p-Akt and p-mTOR). Chemical inhibitors of the mTOR pathway reduced regeneration, which implies that Fak integrates Wnt and integrin signaling to activate mTOR signaling. Activating mTOR signaling by treating mice with insulin-like growth factor 1 (IGF1) after irradiation restored regeneration in epithelia lacking Fak. Fak was required for the increased proliferation observed in Apc-deficient intestinal epithelia, and the abundance of p-Akt and p-mTOR was lower in intestinal epithelia lacking both Apc and Fak as compared with epithelia lacking only Apc. Furthermore, Fak deletion suppressed formation of adenomas in Apc heterozygotes. Together, these observations indicate that Fak links Wnt signaling to mTOR activation in intestinal regeneration and tumorigenesis but is dispensable for intestinal homeostasis, which suggests Fak as a potential target for prevention of colorectal tumorigenesis in high-risk individuals. Commentary by Evan explores the implications of these findings for intestinal biology and disease.

G. H. Ashton, J. P. Morton, K. Myant, T. J. Phesse, R. A. Ridgway, V. Marsh, J. A. Wilkins, D. Athineos, V. Muncan, R. Kemp, K. Neufeld, H. Clevers, V. Brunton, D. J. Winton, X. Wang, R. C. Sears, A. R. Clarke, M. C. Frame, O. J. Sansom, Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling. Dev. Cell. 19, 259269 (2010). [PubMed]

G. Evan, Getting one’s Fak straight. Dev. Cell. 19, 185186 (2010). [PubMed]

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