Thumbnail
Access Restriction
Open

Author Gao, Chenxi ♦ Chen, Guangming ♦ Kuan, Shih-Fan ♦ Zhang, Dennis Han ♦ Schlaepfer, David D. ♦ Hu, Jing
Source Paperity
Content type Text
Publisher eLife Sciences Publications, Ltd
File Format PDF ♦ HTM / HTML
Copyright Year ©2015
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 Wnt-induced 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-GSK3βY216 and β-catenin, indicating that FAK/PYK2/GSK3βY216 axis is critical for the activation of Wnt/β-catenin signaling in APC driven intestinal tumorigenesis.
Learning Resource Type Article
Publisher Date 2015-08-14
e-ISSN 2050084X
Journal eLife