Hippo signaling is an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, apoptosis, and stem cell self-renewal. In addition, dysregulation of the Hippo pathway contributes to cancer development.

The Core of the Mammalian Hippo Pathway

Similar to the invertebrate cascade, a series of phosphorylation events via MST (ortholog of Drosophila Hippo) and Wts (mammalian LATS1/2) ultimately leads to the phosphorylation of two co-activators: YAP and TAZ. Once phosphorylated, the protein kinase is activated, resulting in a series of changes in downstream processes.

Activation of the Mammalian Hippo Pathway

Yorkie (Yki) is a transcriptional co-activator; it cannot be directly combined with DNA, but needs to combine with the transcription factor Scalloped (Sd) to form the Yki-Sd complex, which plays a role in transcription regulation. The Yki-Sd transcription complex can be regulated by multiple genes related to cell proliferation and transcription regulation, such as E cyclin. When the organ reaches a certain size, the pathway is activated and phosphorylated (activated) Wts can be phosphorylated by Yki, and the 168th serine is activated. Yki binds to 14-3-3 after phosphorylation (inactivation). This process allows Yki to reside in the cytoplasm, which cannot form a transcriptional regulatory complex with Sd, and inhibit the transcription of downstream target genes.

In the nucleus, both YAP and TAZ can bind to TEAD1/4 and activate the transcription of genes required to promote cell growth and inhibit apoptosis (CTGF, AREG, BIRC5-2, FGF, and GLI-2). Upon phosphorylation by the SRC/ABL kinases, YAP and TAZ acquire the capacity to bind p73 and activate the transcription of proapoptotic genes. Numerous transcription factors are described as YAP/TAZ binding partners, but their functional significance is still unclear.