Journal
CHEMISTRY & BIOLOGY
Volume 19, Issue 8, Pages 955-962Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2012.07.005
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Funding
- Genomics Institute of the Novartis Research Foundation
- Massachusetts General Hospital institutional fund
- Harvard Stem Cell Institute
- Children's Tumor Foundation
- Novartis Research Foundation
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Hippo signaling represents a tumor suppressor pathway that regulates organ size and tumorigenesis through phosphorylation and inhibition of the transcription coactivator YAP. Here, we show that serum deprivation dramatically induces YAP Ser127 phosphorylation and cytoplasmic retention, independent of cell-cell contact. Through chemical isolation and activity profiling, we identified serum-derived sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) as small molecule activators of YAP. S1P induces YAP nuclear localization through S1P(2) receptor, Rho GTPase activation, and F-actin polymerization, independent of the core Hippo pathway kinases. Bioinformatics studies also showed that S1P stimulation induces YAP target gene expression in mouse liver and human embryonic stem cells. These results revealed potent small molecule regulators of YAP and suggest that Si P and LPA might modulate cell proliferation and tumorigenesis through YAP activation.
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