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

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/GSK3β ^Y216/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 Wnt-induced 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-GSK3β ^Y216 and β-catenin, indicating that FAK/PYK2/GSK3β ^Y216 axis is critical for the activation of Wnt/β-catenin signaling in APC driven intestinal tumorigenesis.

DOI: http://dx.doi.org/10.7554/eLife.10072.001

eLife digest

The cells in our body communicate with each other to coordinate many essential processes, including cell division and the formation of tissues and organs. The Wnt signaling pathway is crucial for cell communication across all animal species, but activating this pathway at the wrong time can cause cancer to develop. As part of the investigation into treatments for colon and other intestinal cancers, researchers have tried to identify drugs that inhibit Wnt signaling. This search would be easier if we understood more about how the Wnt signaling pathway is controlled.

When the protein GSK3 is active, it can switch the Wnt signaling pathway ‘off’, and inactivating GSK3 can turn the Wnt signaling pathway ‘on’. Enzymes known as kinases can inactivate GKS3 by adding a phosphate group to it, in a process known as phosphorylation. It was unknown which kinases phosphorylate GSK3, and whether this affects how cancerous tumors develop in the colon.

Gao, Chen et al. analyzed cells taken from human and mice and observed that two kinases called PYK2 and FAK phosphorylate one form of GSK3, known as GSK3β. Furthermore, both kinases are required to inactivate GSK3β completely, and so turn on the Wnt signaling pathway.

During the early stages of colon cancer, cells first develop into polyps, which subsequently become cancerous. Gao, Chen et al. treated mice that had genetic mutations that made them susceptible to colon cancer with a chemical compound that inhibits both FAK and PYK2. These mice grew fewer polyps than untreated mice, and the polyps that did grow tended to be smaller.

Tissue samples taken from humans in the early stages of colon cancer—as the polyps progress towards becoming cancerous—had high levels of FAK, PYK2 and phosphorylated GSK3β. Overall, this suggests that drugs that simultaneously inhibit FAK and PYK2 may be an effective treatment for colon cancer, although further studies will be needed to confirm this.

DOI: http://dx.doi.org/10.7554/eLife.10072.002