Convergence of Wnt, growth factor, and heterotrimeric G protein signals on the guanine nucleotide exchange factor Daple

The protein Daple coordinates cross-talk among growth factor receptors, Wnt, and G protein–coupled signaling pathways to facilitate tumor progression. Growth factor and Wnt pathways cross-talk on Daple Many proteins that maintain tissue homeostasis are conversely implicated in tumor progression. What triggers this switch? The guanine nucleotide exchange factor Daple, which coordinates Wnt and G protein signals, acts as a tumor suppressor in the normal epithelium and early-stage tumors but facilitates metastatic progression in advanced tumors. Aznar et al. found that growth factor receptor activation, frequently observed in many cancers, phosphorylated a critical protein interaction motif in Daple that enhanced its binding to G proteins rather than to a Wnt receptor inhibitor, thereby stimulating ligand-independent Wnt signaling. Supported by protein signatures in colorectal tumors from patients, these findings suggest that concurrent activation of Wnt and growth factor receptor pathways fuels a Daple-mediated switch to cancer progression. Cellular proliferation, differentiation, and morphogenesis are shaped by multiple signaling cascades, and their dysregulation plays an integral role in cancer progression. Three cascades that contribute to oncogenic potential are those mediated by Wnt proteins and the receptor Frizzled (FZD), growth factor receptor tyrosine kinases (RTKs), and heterotrimeric G proteins and associated GPCRs. Daple is a guanine nucleotide exchange factor (GEF) for the G protein Gαi. Daple also binds to FZD and the Wnt/FZD mediator Dishevelled (Dvl), and it enhances β-catenin–independent Wnt signaling in response to Wnt5a-FZD7 signaling. We identified Daple as a substrate of multiple RTKs and non-RTKs and, hence, as a point of convergence for the three cascades. We found that phosphorylation near the Dvl-binding motif in Daple by both RTKs and non-RTKs caused Daple/Dvl complex dissociation and augmented the ability of Daple to bind to and activate Gαi, which potentiated β-catenin–independent Wnt signals and stimulated epithelial-mesenchymal transition (EMT) similarly to Wnt5a/FZD7 signaling. Although Daple acts as a tumor suppressor in the healthy colon, the concurrent increased abundance of Daple and epidermal growth factor receptor (EGFR) in colorectal tumors was associated with poor patient prognosis. Thus, the Daple-dependent activation of Gαi and the Daple-dependent enhancement of β-catenin–independent Wnt signals are not only stimulated by Wnt5a/FZD7 to suppress tumorigenesis but also hijacked by growth factor–activated RTKs to enhance tumor progression. These findings identify a cross-talk paradigm among growth factor RTKs, heterotrimeric G proteins, and the Wnt/FZD pathway in cancer.