The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain
| Autor: | Richard O. Hynes, Patrick Stern, Zhigang Jiang, John M. Lamar, Jeffrey W. Schindler, Hui Liu |
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| Rok vydání: | 2012 |
| Předmět: |
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Western Regulator Cell Cycle Proteins Mammary Neoplasms Animal Biology Polymerase Chain Reaction Metastasis Mice Transduction Genetic Cell Line Tumor medicine Animals Humans Cloning Molecular Neoplasm Metastasis Luciferases Transcription factor Melanoma Adaptor Proteins Signal Transducing YAP1 Hippo signaling pathway Multidisciplinary Oncogene TEA Domain Transcription Factors YAP-Signaling Proteins medicine.disease Flow Cytometry Phosphoproteins Molecular biology Protein Structure Tertiary DNA-Binding Proteins Retroviridae PNAS Plus Tumor progression Cancer research Mutagenesis Site-Directed Female Signal Transduction Transcription Factors |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 109(37) |
| ISSN: | 1091-6490 |
| Popis: | The transcriptional coactivator Yes-associated protein (YAP) is a major regulator of organ size and proliferation in vertebrates. As such, YAP can act as an oncogene in several tissue types if its activity is increased aberrantly. Although no activating mutations in the yap1 gene have been identified in human cancer, yap1 is located on the 11q22 amplicon, which is amplified in several human tumors. In addition, mutations or epigenetic silencing of members of the Hippo pathway, which represses YAP function, have been identified in human cancers. Here we demonstrate that, in addition to increasing tumor growth, increased YAP activity is potently prometastatic in breast cancer and melanoma cells. Using a Luminex-based approach to multiplex in vivo assays, we determined that the domain of YAP that interacts with the TEAD/TEF family of transcription factors but not the WW domains or PDZ-binding motif, is essential for YAP-mediated tumor growth and metastasis. We further demonstrate that, through its TEAD-interaction domain, YAP enhances multiple processes known to be important for tumor progression and metastasis, including cellular proliferation, transformation, migration, and invasion. Finally, we found that the metastatic potential of breast cancer and melanoma cells is strongly correlated with increased TEAD transcriptional activity. Together, our results suggest that increased YAP/TEAD activity plays a causal role in cancer progression and metastasis. |
| Databáze: | OpenAIRE |
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