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Dev Cell. 2016 Apr 4;37(1):47-57. doi: 10.1016/j.devcel.2016.03.002.

SETD7 Controls Intestinal Regeneration and Tumorigenesis by Regulating Wnt/β-Catenin and Hippo/YAP Signaling.

Author information

1
The Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: menno.oudhoff@ntnu.no.
2
The Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
3
Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
4
The Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
5
The Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
6
Department of Gastroenterology, School of Medicine, Keio University, Tokyo 160-8582, Japan.
7
Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA.
8
Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, USA.
9
The Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
10
The Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia. Electronic address: colby.zaph@monash.edu.

Abstract

Intestinal tumorigenesis is a result of mutations in signaling pathways that control cellular proliferation, differentiation, and survival. Mutations in the Wnt/β-catenin pathway are associated with the majority of intestinal cancers, while dysregulation of the Hippo/Yes-Associated Protein (YAP) pathway is an emerging regulator of intestinal tumorigenesis. In addition, these closely related pathways play a central role during intestinal regeneration. We have previously shown that methylation of the Hippo transducer YAP by the lysine methyltransferase SETD7 controls its subcellular localization and function. We now show that SETD7 is required for Wnt-driven intestinal tumorigenesis and regeneration. Mechanistically, SETD7 is part of a complex containing YAP, AXIN1, and β-catenin, and SETD7-dependent methylation of YAP facilitates Wnt-induced nuclear accumulation of β-catenin. Collectively, these results define a methyltransferase-dependent regulatory mechanism that links the Wnt/β-catenin and Hippo/YAP pathways during intestinal regeneration and tumorigenesis.

PMID:
27046831
DOI:
10.1016/j.devcel.2016.03.002
[Indexed for MEDLINE]
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