Hippo-Yes-associated protein signaling pathway (Hippo/YAP pathway)

The Hippo-Yes-associated protein (YAP) signaling pathway is a highly conserved evolutionary mechanism that serves as a master regulator of organ size, tissue homeostasis, and regeneration [Pan, 2010]. The pathway consists of a core kinase cascade, including MST1/2 and LATS1/2, which acts to phosphorylate and inhibit the transcriptional co-activators YAP and TAZ, thereby sequestering them in the cytoplasm or marking them for degradation [Piccolo et al., 2014]. When the Hippo pathway is "off" or dysregulated, YAP and TAZ translocate to the nucleus, where they partner with TEA domain (TEAD) transcription factors to initiate the expression of genes promoting cell proliferation and survival [Zhao et al., 2010]. In many human malignancies, such as malignant mesothelioma, hepatocellular carcinoma, and breast cancer, the pathway is frequently inactivated through mutations in upstream regulators like NF2 (Merlin), leading to uncontrolled YAP/TAZ activity and tumor growth [Harvey et al., 2013]. Therapeutic interventions are currently focused on small molecules that inhibit the YAP-TEAD interaction, particularly through the targeting of the TEAD palmitoylation pocket, with several candidates currently undergoing clinical evaluation [Dey et al., 2020].

Other names

Hippo-YAP/TAZ pathwaySalvador-Warts-Hippo pathwayMst-Lats signaling pathwaySWH pathway

Inhibition of the YAP/TAZ-TEAD transcriptional complex, primarily through small molecule inhibition of TEAD palmitoylation or disruption of protein-protein interactions between YAP/TAZ and TEAD transcription factors.