FAK/PYK2 promotes the Wnt/β-catenin pathway and intestinal tumorigenesis by phosphorylating GSK3β

Aberrant activation of Wnt/beta-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/GSK3 beta(Y216)/beta-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/beta-catenin pathway by phosphorylating GSK3 beta(Y216) to reinforce pathway output-beta-catenin accumulation and intestinal tumorigenesis. We previously showed that Wnt-induced beta-catenin accumulation requires Wnt-induced GSK3 beta/beta-TrCP interaction; the current study revealed that phosphorylation of GSK3 beta(Y216) was a molecular determinant of GSK3 beta recruitment of beta-TrCP. Pharmacological inhibition of FAK/PYK2 suppressed adenoma formation in APC(min/+) mice accompanied with reduced intestinal levels of phospho-GSK3 beta(Y216) and beta-catenin, indicating that FAK/PYK2/GSK3 beta(Y216) axis is critical for the activation of Wnt/beta-catenin signaling in APC driven intestinal tumorigenesis.