Hippo-YAP/TAZ signaling pathway

The Hippo pathway signaling network, initially discovered approximately 20 years ago by genetic screening in Drosophila, is an important developmental program for controlling cell proliferation and apoptosis. The mammalian Hippo signaling pathway restricts the proliferation of adult stem/progenitor cells and thereby plays key roles in organ size control and regeneration.

The core complex of this pathway comprises the protein kinases MST1 and 2 (MST1/2; the mammalian homologs of Hpo in Drosophila), WW45 (Sav1), MOB1a/b (Mats), LATS1/2 (Warts), and the downstream transcriptional coactivators, YAP and TAZ (YAP/TAZ; Yorkie in Drosophila). Upstream components of the Hippo pathway vary under different contexts and include scaffolding proteins such as Kibra, Merlin, and Expanded. Upon activation of the Hippo pathway by upstream signals, MST1/2 phosphorylate and thereby activate LATS1/2 with the help of SAV1 and MOB1, after which LATS1/2 phosphorylate YAP and TAZ at several motifs, thereby sequestering them in the cytoplasm and rendering them transcriptionally inactive. Conversely, when LATS1/2 activity is inhibited owing to certain growth-promoting signals, unphosphorylated YAP/TAZ are enriched in the nucleus and interact with transcription factors such as TEA domain family proteins (TEADs) to enhance the expression of their target genes.

In the past decade, numerous studies have focused on understanding the physiological roles of the Hippo-YAP/TAZ pathway, identifying its core regulators and upstream signals, and characterizing crucial target genes of YAP/TAZ. Interestingly, unlike typical receptor/ligand-activated signaling pathways, such as epidermal growth factor (EGF), transforming growth factor (TGF)-β or Wnt, the Hippo pathway responds to a myriad of different inputs, including cell-cell contact (density), actin cytoskeletal damage (cell suspension), G-protein–coupled receptor (GPCR) signaling initiated by changes in serum levels or actomyosin stress, and cellular energy status.

Physiological roles of the Hippo-YAP/TAZ signaling pathway

The physiological roles of the Hippo pathway in mammals have been revealed by analyses of the phenotypes of transgenic (Tg) mice conditionally expressing YAP and those with conditional knockout (cKO) of Hippo pathway components. In particular, we and others have generated mice with tissue-specific knockout of MST1/2, SAV1, LATS1/2, or YAP/TAZ in various organs, including the liver, intestine, skin, and heart. Activation of YAP normally leads to hyperproliferation of precursor cells, inhibition of differentiation, proliferation of surrounding cells, and cancer, most notably in the liver, small/large intestine, and stomach. Moreover, YAP is critical for the regeneration of the liver and intestine. Based on these findings, the Hippo-YAP/TAZ signaling pathway can be considered to be crucial not only for development but also for maintaining homeostasis and regeneration.

Mouse Genetics

Modern biology is in the era of mouse genetics. Three aspects are of consideration in choosing model organisms for research: the power of genetics, relevance to human physiology and pathology, and the time of each generation. Even though mice have a short generation and wonderfully reflect human biology, poor genetics has hampered their use. However, during the last two decades, there had been rapid developments in mouse genetics. Now it is possible to artificially manipulate mice genome in a variety of ways: Knock-out (disruption of a gene), conditional knock-out, overexpression of gene, knocking-in wanted DNA segments in the genome.

Taking advantage of the recent development in mouse genetics, we have engineered various transgenic mice in the mammalian Hippo pathway, therefore not confining our research on the cellular level but expanding it to the organism level. In addition to the cell biological approach, the use of the mouse model will provide us a better understanding of gene networks controlling cell fate, and ultimately help treat cancer.