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Alternative Wnt Signaling Activates YAP/TAZ

Hyun Woo Park1, Young Chul Kim2, Bo Yu3

  • 1Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.

Cell
|August 16, 2015
PubMed

Insights

The 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.

Area of Science:

  • Cell biology
  • Molecular biology
  • Cancer research

Background:

  • The transcriptional co-activators YAP and TAZ regulate organ size and tissue homeostasis.
  • Dysregulation of YAP/TAZ is implicated in human cancer.
  • Alternative Wnt signaling pathways play crucial roles in cellular processes.

Purpose of the Study:

  • To identify downstream effectors of the alternative Wnt signaling pathway.
  • To elucidate the mechanism by which alternative Wnt signaling activates YAP/TAZ.
  • To establish YAP/TAZ as mediators of alternative Wnt signaling functions.

Main Methods:

  • Investigated the role of YAP/TAZ in response to Wnt5a/b and Wnt3a.
  • Delineated the signaling cascade from Wnt ligands to YAP/TAZ activation.
  • Assessed YAP/TAZ-mediated functions including gene expression and cell differentiation.

Main Results:

  • YAP/TAZ are bona fide downstream effectors of alternative Wnt signaling.
  • Wnt5a/b and Wnt3a activate YAP/TAZ independently of canonical Wnt/β-catenin signaling.
  • The identified signaling axis involves Wnt-FZD/ROR-Gα12/13-Rho GTPases-Lats1/2.

Conclusions:

  • YAP/TAZ mediate key biological functions of alternative Wnt signaling.
  • Alternative Wnt signaling promotes YAP/TAZ activation and TEAD-mediated transcription.
  • YAP/TAZ are critical mediators of alternative Wnt signaling, impacting gene expression, differentiation, and cell migration.

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