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

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. Sears; A.R. Clarke; M.C. Frame; O.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

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. Sears, A.R. Clarke, M.C. Frame, O.J. Sansom

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

162 Citaten (Scopus)

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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.

Originele taal-2	Engels
Pagina's (van-tot)	259-269
Tijdschrift	Developmental Cell
Volume	19
Nummer van het tijdschrift	2
DOI's	https://doi.org/10.1016/j.devcel.2010.07.015
Status	Gepubliceerd - 2010

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10.1016/j.devcel.2010.07.015

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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., 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

@article{509008bc47a74c0e8203a13257cd7ec3,

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.",

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

note = "Reporting year: 2010 Metis note: S1534-5807(10)00343-6 [pii]",

year = "2010",

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

language = "English",

volume = "19",

pages = "259--269",

journal = "Developmental Cell",

issn = "1534-5807",

publisher = "Cell Press",

number = "2",

}

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, nr. 2, blz. 259-269. https://doi.org/10.1016/j.devcel.2010.07.015

TY - JOUR

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

AU - Ashton, G.H.

AU - Morton, J.P.

AU - Myant, K.

AU - Phesse, T.J.

AU - Ridgway, R.A.

AU - Marsh, V.

AU - Wilkins, J.A.

AU - Athineos, D.

AU - Muncan, V.

AU - Kemp, R.

AU - Neufeld, K.

AU - Clevers, H.

AU - Brunton, V.

AU - Winton, D.J.

AU - Wang, X.

AU - Sears, R.

AU - Clarke, A.R.

AU - Frame, M.C.

AU - Sansom, O.J.

N1 - Reporting year: 2010 Metis note: S1534-5807(10)00343-6 [pii]

PY - 2010

Y1 - 2010

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.

U2 - 10.1016/j.devcel.2010.07.015

DO - 10.1016/j.devcel.2010.07.015

M3 - Article

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

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