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/GSK3β<sup>Y216</sup>/β-catenin regulation axis: FAK and PYK2, elevated in adenomas in APC<sup>min/+</sup> mice and in human colorectal cancer tissues, functioned redundantly to promote the Wnt/β-catenin pathway by phosphorylating GSK3β<sup>Y216</sup> 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 GSK3β<sup>Y216</sup> was a molecular determinant of GSK3β recruitment of β-TrCP. Pharmacological inhibition of FAK/PYK2 suppressed adenoma formation in APC<sup>min/+</sup> mice accompanied with reduced intestinal levels of phospho-GSK3β<sup>Y216</sup> and β-catenin, indicating that FAK/PYK2/GSK3β<sup>Y216</sup> axis is critical for the activation of Wnt/β-catenin signaling in APC driven intestinal tumorigenesis.
Gao, C., Chen, G., Kuan, S. F., Zhang, D. H., Schlaepfer, D. D., & Hu, J. (2015). FAK/PYK2 promotes the Wnt/β-catenin pathway and intestinal tumorigenesis by phosphorylating GSK3β. ELife, 4(AUGUST2015). https://doi.org/10.7554/eLife.10072