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Updated: Jul 8, 2026
Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor (LATS) Biosensor
Published on: September 13, 2018
Tumor suppressor LATS1 is a negative regulator of oncogene YAP
Yawei Hao1, Alex Chun, Kevin Cheung
1Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario K7L 3N6, Canada.
Abstract:
LATS (large tumor suppressor) or warts is a Ser/Thr kinase that belongs to the Ndr/LATS subfamily of AGC (protein kinase A/PKG/PKC) kinases. It is a tumor suppressor gene originally isolated from Drosophila and recently isolated from mice and humans. Drosophila or mice mutant for LATS develop tumors in various tissues. Recent studies in Drosophila demonstrate that LATS is a central player of an emerging tumor suppressor pathway called the Hippo-LATS/Warts pathway that suppresses tumor growth by regulating cell proliferation, cell growth, and cell death. Although tremendous progress has been made toward understanding the roles of LATS in tumorigenesis, the kinase substrates of LATS or downstream target proteins mediating LATS function remain largely unknown. In this study, we have provided convincing evidence that the LATS1 tumor suppressor can bind to and phosphorylate transcription regulator and oncogene YAP in vitro and in vivo. We have also identified HX(R/H/K)XX(S/T) as the consensus phosphorylation sequence for LATS/Ndr kinase substrates. Significantly, we have discovered that LATS1 inactivates YAP oncogenic function by suppressing its transcription regulation of cellular genes via sequestration of YAP in the cytoplasm after phosphorylation of YAP. Finally, by using microarray analysis, we have also identified many oncogenes or tumor suppressor genes up-regulated or down-regulated by YAP. These research findings will have profound impacts on our understanding of the molecular mechanism of the LATS tumor suppressor and the emerging Hippo-LATS/Warts pathway.
Insights
The large tumor suppressor (LATS1) kinase inactivates the oncogenic YAP protein by phosphorylation, preventing its nuclear translocation and thus suppressing tumor growth. This reveals a key mechanism in the Hippo-LATS/Warts tumor suppressor pathway.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- LATS (large tumor suppressor) is a Ser/Thr kinase in the Ndr/LATS subfamily, acting as a tumor suppressor. Mutations in LATS lead to tumor development in various tissues.
- The Hippo-LATS/Warts pathway is crucial for regulating cell proliferation, growth, and apoptosis, thereby suppressing tumor formation.
- While LATS's role in tumorigenesis is recognized, its specific kinase substrates and downstream effectors remain largely unidentified.
Purpose of the Study:
- To investigate the interaction between the LATS1 tumor suppressor and the oncogenic transcription regulator YAP.
- To identify the consensus phosphorylation sequence for LATS/Ndr kinase substrates.
- To elucidate the mechanism by which LATS1 regulates YAP function and its impact on oncogenes and tumor suppressor genes.
Main Methods:
- In vitro and in vivo binding and phosphorylation assays to study LATS1-YAP interaction.
- Identification of the consensus phosphorylation motif for LATS/Ndr kinase substrates.
- Microarray analysis to identify genes regulated by YAP.
Main Results:
- LATS1 directly binds to and phosphorylates YAP both in vitro and in vivo.
- The consensus phosphorylation sequence for LATS/Ndr kinase substrates was identified as HX(R/H/K)XX(S/T).
- Phosphorylation by LATS1 leads to YAP sequestration in the cytoplasm, inactivating its oncogenic transcriptional activity and affecting downstream gene expression.
Conclusions:
- LATS1 directly regulates YAP, a key oncogene, through phosphorylation, thereby inhibiting its function in transcription regulation.
- This phosphorylation-dependent cytoplasmic sequestration of YAP is a critical mechanism for LATS1-mediated tumor suppression.
- The findings deepen the understanding of the Hippo-LATS/Warts pathway and provide insights into potential therapeutic strategies for YAP-driven cancers.
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