Abstract
The transcriptional coactivators YAP/TAZ mediate the biologic responses of alternative WNT signaling.
Major finding: The transcriptional coactivators YAP/TAZ mediate the biologic responses of alternative WNT signaling.
Mechanism: WNT ligands activate a FZD/ROR–Gα12/13–RHO GTPase cascade to inhibit LATS1/2 and activate YAP/TAZ.
Impact: This alternative WNT pathway may provide therapeutic targets to limit tumor growth and metastasis.
WNT proteins regulate a variety of signaling pathways that control development and tissue homeostasis. Canonical WNT signaling utilizes β-catenin/TCF as transcription factors for downstream signal transduction, but effectors of alternative WNT signaling are less clearly defined. Park and colleagues characterized the YAP/TAZ transcriptional coactivators as downstream effectors of the alternative WNT signaling pathway. The WNT ligands WNT3A and WNT5A/B stabilized YAP/TAZ protein levels, induced their nuclear translocation, and resulted in YAP/TAZ target gene expression. Pharmacologic or genetic perturbation of canonical WNT/β-catenin signaling did not affect YAP/TAZ stability or activity, supporting the hypothesis that YAP/TAZ are exclusively activated via the alternative WNT signaling axis. Activation of YAP/TAZ was mediated by signaling of the Frizzled (FZD) receptor family and retinoic acid–related orphan receptors (ROR) via the G proteins Gα 12/13, as depletion of Gα 12/13 attenuated WNT3A-mediated YAP/TAZ activation. Similarly, mutation or inhibition of the RHO GTPases RHOA and RAC1 blocked WNT3A- and FZD-induced YAP/TAZ activation. Activated RHOA inhibited LATS1/2 kinases, which reduced their inhibitory phosphorylation of YAP/TAZ, demonstrating that FZD/ROR–driven activation of G-protein signaling promotes nuclear translocation and activation of YAP/TAZ. YAP/TAZ were required for alternative WNT–induced osteogenic differentiation and cell migration. Furthermore, activation of YAP/TAZ decreased the accumulation of β-catenin and β-catenin/TCF target gene expression; this inhibition was the result of YAP/TAZ–TEAD-mediated transcriptional upregulation of secreted factors known to block canonical WNT/β-catenin signaling, including WNT5A/B. Consistent with these findings, YAP/TAZ promoted adipogenesis by suppressing the anti-adipogenic effects of canonical WNT/β-catenin signaling, and YAP/TAZ–TEAD was required for WNT5A induction in PIK3CA-mutant cells. Overall, these data identify YAP/TAZ as transcriptional coactivators that mediate the biologic functions of the alternative WNT signaling axis and antagonize canonical WNT/β-catenin signaling.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.