YAP controls cell migration and invasion through a Rho-GTPase switch

SUMMARY Understanding the mechanisms controlling the invasive spread of normal and transformed cells is central to understanding diverse processes including cancer progression. Here, we report that Yes- associated protein (YAP), a central transcriptional regulator implicated in controlling organ and body size, modulates a Rho-GTPase switch that drives cellular migration by directly transactivating the Rac1-GEF protein TRIO. Additionally, YAP and TRIO activate the Rac1-STAT3 axis to promote invasive behavior. While we find this YAP-dependent infiltrative program in many cell types, it is particularly enhanced in a patient-specific way in the most common malignant brain tumor, glioblastoma (GBM), where hyperactivation of the YAP-mediated TRIO and STAT3 network also confers poor patient outcome and up-regulation of genes associated with the Mesenchymal subtype of GBM. Our analysis suggests that the YAP-TRIO-STAT3 signaling network identified in this study is a ubiquitous regulator of invasive cell spread in both normal and pathological contexts.