Role of YAP/TAZ in conferring cellular plasticity
During the creation and analysis of upstream Hippo pathway component knockout mice, our group discovered that differentiated cells of certain types of tissues can transdifferentiate into other cell types. Moreover, in certain tissues undergoing regeneration, we found that YAP was highly active and that these regenerating cells were in the process of transdifferentiating. These results strongly suggest that YAP activation confers cell plasticity, even to fully differentiated cells. With recent advances in methods such as single-cell RNA sequencing, tracing the lineage of different cell types has never been easier.
Role of YAP/TAZ in cancer
Due to their prominent role in regeneration and development, deregulation of YAP/TAZ is implicated in various cancers. Specifically, they are activated in various cancers of the epithelium, and YAP activation is a defining characteristic of cancer stem cells. YAP activation leads to increases in motility and modifications of the microenvironment that serve to support the proliferation of neighboring fibroblasts. The best-known target genes of YAP/TAZ include secretory factors, regulators of actin/cytoskeleton dynamics, and genes involved in cell proliferation, migration, and tumor metastasis.
Mechanisms governing the regulation of the Hippo-YAP/TAZ signaling pathway
A number of upstream stimuli have been shown to regulate the Hippo-YAP/TAZ signaling pathway, including cell-cell contact, cell junction, and density, and GPCR signaling. At the core of these inputs lies RhoA, which itself is regulated by mechanical cues. However, the mechanism by which RhoA controls the kinase activity of LATS1/2 remains unclear. We are eagerly working to fully characterize the relationship between RhoA and LATS1/2, and identify other related proteins to assess the physiological significance of this network.
Identification of novel molecules that affect YAP/TAZ activity
YAP/TAZ not only interact with TEAD transcription factors (TEAD1–4), but also bind to other transcription factors, such as SRF, MYC, and c-FOS to drive target gene expression. In fact, enhancer-mediated chromosomal looping enables YAP/TAZ/TEAD to co-occupy chromatin regions with SRF/MRTF, MYC, and c-FOS, and regulate target gene expression. To search for other novel players within this complicated network, we are employing unbiased screening approaches, utilizing modern techniques such as high-throughput CRISPR/Cas9-mediated genome editing.