1. Biochemistry and Chemical Biology
  2. Cell Biology
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FAK/PYK2 Promotes the Wnt/B-catenin pathway and intestinal tumorigenesis by phosphorylating GSK3β

  1. Chenxi Gao
  2. Guangming Chen
  3. Shih-Fan Kuan
  4. Dennis Han Zhang
  5. David D Schlaepfer
  6. Jing Hu  Is a corresponding author
  1. University of Pittsburgh School of Medicine, United States
  2. Dietrich School of Arts and Sciences, United States
  3. University of California, San Diego, United States
Research Article
  • Cited 61
  • Views 3,646
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Cite this article as: eLife 2015;4:e10072 doi: 10.7554/eLife.10072

Abstract

Aberrant activation of Wnt/β-catenin signaling plays an unequivocal role in colorectal cancer, but identification of effective Wnt inhibitors for use in cancer remains a tremendous challenge. New insights into the regulation of this pathway could reveal new therapeutic point of intervention, therefore are greatly needed. Here we report a novel FAK/PYK2/GSK3βY216/β-catenin regulation axis: FAK and PYK2, elevated in adenomas in APCmin/+ mice and in human colorectal cancer tissues, functioned redundantly to promote the Wnt/β-catenin pathway by phosphorylating GSK3βY216 to reinforce pathway output-β-catenin accumulation and intestinal tumorigenesis. We previously showed that Wnt-induced β-catenin accumulation requires Wntinduced GSK3β/β-TrCP interaction; the current study revealed that phosphorylation of GSK3βY216 was a molecular determinant of GSK3β recruitment of β-TrCP. Pharmacological inhibition of FAK/PYK2 suppressed adenoma formation in APCmin/+ mice accompanied with reduced intestinal levels of phospho-SK3βY216 and β-catenin, indicating that FAK/PYK2/GSK3βY216 axis is critical for the activation of Wnt/β-catenin signaling in APCdriven intestinal tumorigenesis.

Article and author information

Author details

  1. Chenxi Gao

    Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Guangming Chen

    Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Shih-Fan Kuan

    Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Dennis Han Zhang

    Dietrich School of Arts and Sciences, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. David D Schlaepfer

    Department of Reproductive Medicine, Moores Cancer Center, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jing Hu

    Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States
    For correspondence
    huj3@upmc.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#14013138) of the University of Pittsburgh.

Reviewing Editor

  1. Jonathan A Cooper, Fred Hutchinson Cancer Research Center, United States

Publication history

  1. Received: July 14, 2015
  2. Accepted: August 11, 2015
  3. Accepted Manuscript published: August 14, 2015 (version 1)
  4. Version of Record published: September 3, 2015 (version 2)

Copyright

© 2015, Gao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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