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PMID: 20708588 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Developmental cell ·Vol. 19 ·No. 2 ·2010-08-17 ·Pages 259-69

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 RC, Clarke AR, Frame MC, Sansom OJ

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.

MeSH Terms
Animals Focal Adhesion Protein-Tyrosine Kinases/genetics,metabolism Humans Intestinal Neoplasms/metabolism,pathology Intestines/pathology,physiology Intracellular Signaling Peptides and Proteins/genetics,metabolism Male Mice Mice, Inbred C57BL Protein Serine-Threonine Kinases/genetics,metabolism Proto-Oncogene Proteins c-akt/genetics,metabolism Proto-Oncogene Proteins c-myc/genetics,metabolism Regeneration Signal Transduction/physiology TOR Serine-Threonine Kinases Wnt Proteins/genetics,metabolism
Chemicals
Intracellular Signaling Peptides and Proteins Proto-Oncogene Proteins c-myc Wnt Proteins MTOR protein, human mTOR protein, mouse Focal Adhesion Protein-Tyrosine Kinases Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt TOR Serine-Threonine Kinases
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Ashton Gabrielle H
The Beatson Institute for Cancer Research, Glasgow, UK.
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 C
Clarke Alan R
Frame Margaret C
Sansom Owen J
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Article Info
Journal
Developmental cell
Abbr.
Dev Cell
ISSN
1878-1551
DOI
10.1016/j.devcel.2010.07.015
Published
2010-08-17
Pages
259-69
Language
English
Region
United States
NLM ID
101120028
PMCID
PMC3291717
Subset
IM
Grants
Cancer Research UK · C157/A9148 · United Kingdom
NCI NIH HHS · R01 CA129040-01A2 · United States
NCI NIH HHS · R01 CA129040 · United States
Worldwide Cancer Research · 10-0643 · United Kingdom
Cancer Research UK · C1295/A9590 · United Kingdom
Corrections
CommentIn
PMID: 20708578
External Links
PubMed source DOI: 10.1016/j.devcel.2010.07.015 PMC Full Text View journal details
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