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Updated: Jun 5, 2026
Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor (LATS) Biosensor
Published on: September 13, 2018
Snapshots of a hybrid transcription factor in the Hippo pathway
1Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA. xuelian.luo@utsouthwestern.edu
Abstract:
The Hippo pathway plays key roles in animal development. It suppresses tumorigenesis by controlling the transcription of the target genes that are critical for cell proliferation and apoptosis. The transcriptional coactivator YAP is the major downstream effector of the Hippo signaling. Upon extracellular stimulation, a kinase cascade in the Hippo pathway phosphorylates YAP and promotes its cytoplasmic sequestration by 14-3-3 and ubiquitin-dependent degradation. When the Hippo pathway is turned off, YAP (which lacks a DNA-binding domain) is dephosphorylated and translocates to the nucleus, where it associates with the transcription factor TEAD to form a functional heterodimeric transcription factor and to promote the expression of the Hippo-responsive genes. Recently, structures of the YAP-binding domain of TEAD alone or in complex with YAP have revealed the atomic details of the TEAD-YAP interaction. Here, I review these exciting advances, propose a strategy for targeting the TEAD-YAP interaction using small molecules, and suggest potential mechanisms by which phosphorylation and 14-3-3 binding regulate the cytoplasmic retention of YAP.
Insights
The Hippo pathway regulates animal development and suppresses tumors. YAP, a key effector, forms a transcription factor with TEAD, and targeting this interaction offers a novel therapeutic strategy.
Area of Science:
- Cell biology
- Molecular biology
- Developmental biology
Background:
- The Hippo pathway is crucial for animal development and tumor suppression.
- It controls gene transcription regulating cell proliferation and apoptosis.
- YAP is the primary downstream effector, mediating Hippo signaling outcomes.
Purpose of the Study:
- To review recent structural insights into the TEAD-YAP interaction.
- To propose small molecule strategies targeting the TEAD-YAP complex.
- To explore YAP regulation by phosphorylation and 14-3-3 binding.
Main Methods:
- Structural biology (crystallography) of TEAD-YAP complexes.
- Review of signaling pathways regulating YAP localization and activity.
- Bioinformatic and medicinal chemistry approaches for drug design.
Main Results:
- Atomic structures reveal the YAP-binding domain of TEAD and its complex with YAP.
- YAP's nuclear translocation and TEAD association are critical for Hippo-responsive gene expression.
- Phosphorylation and 14-3-3 binding mediate YAP's cytoplasmic retention.
Conclusions:
- Targeting the TEAD-YAP interaction is a promising strategy for cancer therapy.
- Understanding YAP regulation provides insights into developmental processes.
- Structural data facilitates the rational design of small molecule inhibitors.
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