Fig. 1

The Hippo signaling pathway and therapeutic targets. The Hippo signaling pathway consists of the kinase cascade component in the cytoplasm and the YAP/TAZ-TEAD transcription component in the nucleus. The pathway is regulated by numerous stimuli, including mechanical stress, GPCRs, cell polarity, and cell adhesion. When the Hippo pathway is “on,” the kinase cascade transduces the stimuli, ending with YAP/TAZ phosphorylation. Phosphorylated YAP/TAZ bind with 14–3-3 and undergo ubiquitin-proteasomal degradation. In the Hippo “off” condition, YAP/TAZ are activated in a dephosphorylated state and are translocated into the nucleus to modulate transcription. The possible targets of the Hippo pathway are: i) upstream regulators of YAP/TAZ, ii) YAP/TAZ nuclear translocation, iii) protein–protein interaction between YAP/TAZ and TEAD, iv) protein-DNA interaction between YAP/TAZ-TEAD and target DNA, and v) transcription and expression of the target genes. Candidate compounds shown in the diagram are ACT-333679, DHX, statins, MK-5108, verteporfin, and miR-15a. The GPCR ligands are ACT-333679, which is a partial agonist of IP receptor, and DHX, which is a full agonist of DRD1. The statins are HMG-CoA reductase inhibitors and MK-5108, which is a selective inhibitor for Aurora kinase A; they indirectly inhibit the nuclear translocation of YAP. Verteporfin blocks the protein–protein interaction of YAP/TAZ and TEAD, and MiR-15a decreases YAP expression