FAK/PYK2 Promotes the Wnt/B-catenin pathway and intestinal tumorigenesis by phosphorylating GSK3β

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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 APC^min/+ mice and in human colorectal cancer tissues, functioned redundantly to promote the Wnt/β-catenin pathway by phosphorylating GSK3β^Y216 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 GSK3β^Y216 was a molecular determinant of GSK3β recruitment of β-TrCP. Pharmacological inhibition of FAK/PYK2 suppressed adenoma formation in APC^min/+ mice accompanied with reduced intestinal levels of phospho-SK3β^Y216 and β-catenin, indicating that FAK/PYK2/GSK3β^Y216 axis is critical for the activation of Wnt/β-catenin signaling in APCdriven intestinal tumorigenesis.

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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.
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.
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.
Dennis Han Zhang

Dietrich School of Arts and Sciences, Pittsburgh, United States

Competing interests
The authors declare that no competing interests exist.
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.
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.

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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.