Alternative Wnt Signaling Activates YAP/TAZ

• Wnt ligands promote YAP/TAZ activation via the alternative Wnt signaling pathway
• Alternative Wnt-YAP/TAZ signaling consists of Wnt-FZD/ROR-Gα12/13-Rho-Lats1/2-YAP/TAZ
• YAP/TAZ mediate alternative Wnt signaling-induced osteogenesis and cell migration
• YAP/TAZ antagonize Wnt/β-catenin signaling by inducing secreted Wnt inhibitors

SummaryThe transcriptional co-activators YAP and TAZ are key regulators of organ size and tissue homeostasis, and their dysregulation contributes to human cancer. Here, we discover YAP/TAZ as bona fide downstream effectors of the alternative Wnt signaling pathway. Wnt5a/b and Wnt3a induce YAP/TAZ activation independent of canonical Wnt/β-catenin signaling. Mechanistically, we delineate the “alternative Wnt-YAP/TAZ signaling axis” that consists of Wnt-FZD/ROR-Gα12/13-Rho GTPases-Lats1/2 to promote YAP/TAZ activation and TEAD-mediated transcription. YAP/TAZ mediate the biological functions of alternative Wnt signaling, including gene expression, osteogenic differentiation, cell migration, and antagonism of Wnt/β-catenin signaling. Together, our work establishes YAP/TAZ as critical mediators of alternative Wnt signaling.

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