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

doi:10.1016/j.devcel.2010.07.015

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

Molecular and Medical Genetics

Research output: Contribution to journal › Article › peer-review

160 Scopus citations

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 language	English (US)
Pages (from-to)	259-269
Number of pages	11
Journal	Developmental Cell
Volume	19
Issue number	2
DOIs	https://doi.org/10.1016/j.devcel.2010.07.015
State	Published - Aug 2010

Keywords

Cellcycle
Humdisease

ASJC Scopus subject areas

Molecular Biology
General Biochemistry, Genetics and Molecular Biology
Developmental Biology
Cell Biology

Access to Document

10.1016/j.devcel.2010.07.015

Cite this

Ashton, G. H., Morton, J. P., Myant, K., Phesse, T. J., Ridgway, R. A., Marsh, V., Wilkins, J. A., Athineos, D., Muncan, V., Kemp, R., Neufeld, K., Clevers, H., Brunton, V., Winton, D. J., Wang, X., Sears, R. C., Clarke, A. R., Frame, M. C., & 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

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 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

@article{9b0ab48ffd9449e696eab3e18c9a675e,

title = "Focal Adhesion Kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling",

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.",

keywords = "Cellcycle, Humdisease",

author = "Ashton, {Gabrielle H.} and Morton, {Jennifer P.} and Kevin Myant and Phesse, {Toby J.} and Ridgway, {Rachel A.} and Victoria Marsh and Wilkins, {Julie A.} and Dimitris Athineos and Vanesa Muncan and Richard Kemp and Kristi Neufeld and Hans Clevers and Valerie Brunton and Winton, {Douglas J.} and Xiaoyan Wang and Sears, {Rosalie C.} and Clarke, {Alan R.} and Frame, {Margaret C.} and Sansom, {Owen J.}",

note = "Funding Information: This work was supported by CR-UK. O.J.S. is core funded by CR-UK (Beatson Institute), while A.R.C. (C1295/A9590), M.C.F. (C157/A9148), and V.B. (C157/A9148) are supported by their CR-UK program grants. Generation of the Rosa Floxed Stop (RFS)-Myc mice was supported by the Susan G. Komen Breast Cancer Foundation awards BCTR0201697 and BCTR0706821 to R.C.S. and the Department of Defense Breast Cancer research program award BC061306 to R.C.S. ",

year = "2010",

month = aug,

doi = "10.1016/j.devcel.2010.07.015",

language = "English (US)",

volume = "19",

pages = "259--269",

journal = "Developmental Cell",

issn = "1534-5807",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - Focal Adhesion Kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling

AU - Ashton, Gabrielle H.

AU - Morton, Jennifer P.

AU - Myant, Kevin

AU - Phesse, Toby J.

AU - Ridgway, Rachel A.

AU - Marsh, Victoria

AU - Wilkins, Julie A.

AU - Athineos, Dimitris

AU - Muncan, Vanesa

AU - Kemp, Richard

AU - Neufeld, Kristi

AU - Clevers, Hans

AU - Brunton, Valerie

AU - Winton, Douglas J.

AU - Wang, Xiaoyan

AU - Sears, Rosalie C.

AU - Clarke, Alan R.

AU - Frame, Margaret C.

AU - Sansom, Owen J.

N1 - Funding Information: This work was supported by CR-UK. O.J.S. is core funded by CR-UK (Beatson Institute), while A.R.C. (C1295/A9590), M.C.F. (C157/A9148), and V.B. (C157/A9148) are supported by their CR-UK program grants. Generation of the Rosa Floxed Stop (RFS)-Myc mice was supported by the Susan G. Komen Breast Cancer Foundation awards BCTR0201697 and BCTR0706821 to R.C.S. and the Department of Defense Breast Cancer research program award BC061306 to R.C.S.

PY - 2010/8

Y1 - 2010/8

N2 - 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.

AB - 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.

KW - Cellcycle

KW - Humdisease

UR - http://www.scopus.com/inward/record.url?scp=77955587900&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77955587900&partnerID=8YFLogxK

U2 - 10.1016/j.devcel.2010.07.015

DO - 10.1016/j.devcel.2010.07.015

M3 - Article

C2 - 20708588

AN - SCOPUS:77955587900

SN - 1534-5807

VL - 19

SP - 259

EP - 269

JO - Developmental Cell

JF - Developmental Cell

IS - 2

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this