The Hippo pathway is an emerging tumour suppressor pathway that regulates cell proliferation, stem cell functions and organ size.
The Hippo pathway transduces signals from diverse transmembrane inputs such as the cell adhesion and cell polarity receptors E-cadherin, FAT and Crumbs, as well as G protein-coupled receptors (GPCRs), through a kinase cascade that regulates the subcellular localization and activities of the transcriptional co-activators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ).
YAP and TAZ promote cell proliferation and organ growth. Hyperactivation or overexpression of YAP in mouse models causes overgrowth of various organs and can lead to the development of cancer in the liver, skin and intestine.
YAP and TAZ act as oncogenes and are hyperactivated or overexpressed with a high frequency in many common human cancers. YAP and TAZ promote multiple cancer cell phenotypes, including proliferation, migration and resistance to apoptosis.
Direct or indirect inhibition of YAP and TAZ is a promising novel targeted approach for cancer therapy, and small-molecule modulators of the Hippo pathway have been discovered. Pharmacological modulation of YAP has been shown to be effective for reverting YAP-driven overgrowth phenotypes in mouse models.
Further research is required to test whether small molecules targeting YAP and TAZ are active against human cancer cells and in mouse models that more accurately recapitulate the genetic defects of human tumours.
By contrast, drugs that stimulate YAP and TAZ activity may be useful for stem cell expansion and tissue repair following injury. YAP is activated during the regeneration of the intestinal epithelium, and experimental activation of YAP promotes the capacity of the mouse heart to regenerate.
The Hippo signalling pathway is an emerging growth control and tumour suppressor pathway that regulates cell proliferation and stem cell functions. Defects in Hippo signalling and hyperactivation of its downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) contribute to the development of cancer, which suggests that pharmacological inhibition of YAP and TAZ activity may be an effective anticancer strategy. Conversely, YAP and TAZ can also have beneficial roles in stimulating tissue repair and regeneration following injury, so their activation may be therapeutically useful in these contexts. A complex network of intracellular and extracellular signalling pathways that modulate YAP and TAZ activities have recently been identified. Here, we review the regulation of the Hippo signalling pathway, its functions in normal homeostasis and disease, and recent progress in the identification of small-molecule pathway modulators.
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The authors declare no competing financial interests.
Invasive neoplasms or tumours. Malignant tumours invade neighbouring tissues and have the potential to spread to other tissues.
- Transcriptional co-activators
Proteins that stimulate gene expression but that cannot bind to DNA itself and are instead recruited to DNA by binding to another DNA-binding transcription factor.
- Imaginal discs
Disc-like structures of epithelial cells found in insect larvae that proliferate during the larval stages to around 100,000 cells and then differentiate into various adult structures during metamorphosis. The simplicity of their single-cell layered structure and the ease of genetic manipulation and observation made Drosophila melanogaster imaginal discs into a prominent model system to study cell proliferation, growth control, tissue patterning and cell type specification.
Abnormal growth of tissue that exceeds surrounding tissues and stops responding properly to appropriate growth-inhibitory signals.
Primary or immortalized mammary epithelial cells that can be grown under anchorage-independent conditions to generate spheres of cells. The mammosphere or related tumoursphere assay is often used to detect stem cells in mixed populations of stem and progenitor cells. Transient amplifying or differentiated cells have a limited ability to form mammospheres, whereas bona fide stem cells can generate spheres that can be passaged beyond ten generations.
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Johnson, R., Halder, G. The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nat Rev Drug Discov 13, 63–79 (2014). https://doi.org/10.1038/nrd4161
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