The Hippo Pathway and YAP/TAZ–TEAD Protein–Protein Interaction as Targets for Regenerative Medicine and Cancer Treatment

Abstract

The Hippo pathway is an important organ size control signaling network and the major regulatory mechanism of cell-contact inhibition. Yes associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are its targets and terminal effectors: inhibition of the pathway promotes YAP/TAZ translocation to the nucleus, where they interact with transcriptional enhancer associate domain (TEAD) transcription factors and coactivate the expression of target genes, promoting cell proliferation. Defects in the pathway can result in overgrowth phenotypes due to deregulation of stem-cell proliferation and apoptosis; members of the pathway are directly involved in cancer development. The pharmacological regulation of the pathway might be useful in cancer prevention, treatment, and regenerative medicine applications; currently, a few compounds can selectively modulate the pathway. In this review, we present an overview of the Hippo pathway, the sequence and structural analysis of YAP/TAZ, the known pharmacological modulators of the pathway, especially those targeting YAP/TAZ-TEAD interaction.

Drug development against the hippo pathway in mesothelioma

“…Two small molecule inhibitors that block the YAP-TEAD interaction were identified from John Hopkins Drug Library by drug screening (42). Both Verteporfin (VP, trade name Visudyne by Novartis) and protoporphyrin IX (PPIX) inhibit the YAP-TEAD complex formation at 10 μM in Co-immunoprecipitation assays (43). VP is a FDA-approved photosensitizer in the photodynamic therapy of neovascular macular degeneration; however, when used as an inhibitor of the YAP-TEAD interaction, light activation is not required (43,44).…”

“…Both Verteporfin (VP, trade name Visudyne by Novartis) and protoporphyrin IX (PPIX) inhibit the YAP-TEAD complex formation at 10 μM in Co-immunoprecipitation assays (43). VP is a FDA-approved photosensitizer in the photodynamic therapy of neovascular macular degeneration; however, when used as an inhibitor of the YAP-TEAD interaction, light activation is not required (43,44). VP alters YAP conformation when binding to it, and abolished its interaction to TEAD (45).…”

Prognostic significance of TAZ expression in various cancers: a meta-analysis

“…Transcriptional coactivator with PDZ-binding motif (TAZ; also known by gene name WW domain-containing transcription regulator 1, WWTR1) functions as a key effector in Hippo pathway cascade, which controls the balance between proliferation and apoptosis and regulates organ size through interaction with various transcription factors, particularly TEA domain family members 1. It has been well-documented that TAZ is involved in many cellular progresses, such as induction of proliferation, migration and increased metastatic potential, and inhibition of apoptosis, among others 2,3.…”

The emerging role of YAP/TAZ in mechanotransduction

“…Phosphorylation of S127 of YAP/TAZ is considered an exclusion signal for nuclear accumulation, leading to ubiquitination (1,3,4). Hence, activation of the Hippo pathway leads to inhibition of YAP/TAZ proteins.…”

“…Upstream regulators of the Hippo pathway are Merlin, which is encoded by NF2. In confluent cells, Merlin/NF2 are preferentially localised in close proximity to adherens and tight junctions, and this location has been associated with the known activation of the Hippo pathway and inhibition of YAP/TAZ in cell-cell contact inhibition (1,3,4). YAP/TAZ is a known sensor for mechanical stimuli including matrix stiffness, stretch and cell density.…”