Two-signal requirement for growth-promoting function of Yap in hepatocytes.

The transcriptional coactivator Yes-associated protein (Yap) promotes proliferation and inhibits apoptosis， suggesting that Yap functions as an oncogene. Most oncogenes， however， require a combination of at least two signals to promote proliferation. In this study， we present evidence that Yap activation is insufficient to promote growth in the otherwise normal tissue. Using a mosaic mouse model， we demonstrate that Yap overexpression in a fraction of hepatocytes does not lead to their clonal expansion， as proliferation is counterbalanced by increased apoptosis. To shift the activity of Yap towards growth， a second signal provided by tissue damage or inflammation is required. In response to liver injury， Yap drives clonal expansion， suppresses hepatocyte differentiation， and promotes a progenitor phenotype. These results suggest that Yap activation is insufficient to promote growth in the absence of a second signal thus coordinating tissue homeostasis and repair.