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The TGFβ→TAK1→LATS→YAP1 Pathway Regulates the Spatiotemporal Dynamics of YAP1.
Min-Kyu Kim1,2, Sang-Hyun Han1,2, Tae-Geun Park1
1Department of Biochemistry, College of Medicine and Institute for Tumour Research, Chungbuk National University, Cheongju 28644, Korea.
Molecules and Cells
|September 14, 2023
Summary
Transforming growth factor beta (TGFβ) activates the Hippo pathway via TAK1, leading to YAP1 phosphorylation and nuclear complex formation. This newly identified TGFβ-TAK1-LATS1/2-YAP1 cascade regulates cellular responses and is often disrupted in cancer.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Biology
Background:
- The Hippo kinase cascade regulates cellular responses by controlling Yes-associated protein 1 (YAP1) activity.
- The precise mechanisms by which extracellular signals are translated into intracellular responses by the Hippo pathway are not fully understood.
Purpose of the Study:
- To elucidate the mechanism by which transforming growth factor beta (TGFβ) signaling integrates with the Hippo pathway.
- To identify novel roles for YAP1 phosphorylation in TGFβ-mediated cellular responses.
Main Methods:
- Investigated the interaction between TGFβ signaling components and the Hippo pathway kinases.
- Utilized biochemical assays and cellular localization studies to track YAP1 dynamics.
- Analyzed the formation of protein complexes involving YAP1 and its binding partners.
Main Results:
- TGFβ-activated TAK1 phosphorylates and activates LATS1/2, which subsequently phosphorylates YAP1.
- Phosphorylated YAP1 (p-YAP1) forms a complex with RUNX3, activating target genes in the nucleus before cytoplasmic export.
- Upon TGFβ signal attenuation, unphosphorylated YAP1 forms a distinct complex with TEAD4, SMAD3, AP1, and p300 in the nucleus.
- The dynamic regulation of YAP1 by TGFβ is frequently impaired in cancer cells.
Conclusions:
- Identified a novel signaling cascade integrating TGFβ and Hippo pathways: TGFβ→TAK1→LATS1/2→YAP1.
- Demonstrated a dynamic, spatiotemporal role for phosphorylated YAP1 in the nucleus.
- Highlighted the disruption of this pathway in cancer, suggesting potential therapeutic targets.
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