Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling.
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.
Ashton
Gabrielle H
GH
The Beatson Institute for Cancer Research, Glasgow, UK.
Morton
Jennifer P
JP
Myant
Kevin
K
Phesse
Toby J
TJ
Ridgway
Rachel A
RA
Marsh
Victoria
V
Wilkins
Julie A
JA
Athineos
Dimitris
D
Muncan
Vanesa
V
Kemp
Richard
R
Neufeld
Kristi
K
Clevers
Hans
H
Brunton
Valerie
V
Winton
Douglas J
DJ
Wang
Xiaoyan
X
Sears
Rosalie C
RC
Clarke
Alan R
AR
Frame
Margaret C
MC
Sansom
Owen J
OJ
D000818:Animals; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007414:Intestinal Neoplasms / Q000378:metabolism* / Q000473:pathology; D007422:Intestines / Q000473:pathology / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D016271:Proto-Oncogene Proteins c-myc; D051153:Wnt Proteins; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051416:Focal Adhesion Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases