The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain.
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.
Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
John M
JM
Lamar
Patrick
P
Stern
Hui
H
Liu
Jeffrey W
JW
Schindler
Zhi-Gang
ZG
Jiang
Richard O
RO
Hynes
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008156:Luciferases; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009362:Neoplasm Metastasis / Q000235:genetics*; D010750:Phosphoproteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D012190:Retroviridae; D015398:Signal Transduction / Q000235:genetics*; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D014161:Transduction, Genetic; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D000091262:TEA Domain Transcription Factors; C083215:Tead1 protein, mouse; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D008156:Luciferases