ABSTRACT
The Hippo signaling pathway is a highly conserved signaling network that plays a central role in regulating cellular growth, proliferation, and organ size. This pathway consists of a kinase cascade that integrates various upstream signals to control the activation or inactivation of YAP/TAZ proteins. Phosphorylated YAP/TAZ is sequestered in the cytoplasm; however, when the Hippo pathway is deactivated, it translocates into the nucleus, where it associates with TEAD transcription factors. This partnership is instrumental in regulating the transcription of progrowth and antiapoptotic genes. Thus, in many cancers, aberrantly hyperactivated YAP/TAZ promotes oncogenesis by contributing to cancer cell proliferation, metastasis, and therapy resistance. Because YAP and TAZ exert their oncogenic effects by binding with TEAD, it is critical to understand this key interaction to develop cancer therapeutics. Previous research has indicated that TEAD undergoes autopalmitoylation at a conserved cysteine, and small molecules that inhibit TEAD palmitoylation disrupt effective YAP/TAZ binding. However, how exactly palmitoylation contributes to YAP/TAZ-TEAD interactions and how the TEAD palmitoylation inhibitors disrupt this interaction remains unknown. Utilizing molecular dynamics simulations, our investigation not only provides detailed atomistic insight into the YAP/TAZ-TEAD dynamics but also unveils that the inhibitor studied influences the binding of YAP and TAZ to TEAD in distinct manners. This discovery has significant implications for the design and deployment of future molecular interventions targeting this interaction.
Subject(s)
Lipoylation , Molecular Dynamics Simulation , TEA Domain Transcription Factors , Transcription Factors , Transcriptional Coactivator with PDZ-Binding Motif Proteins , YAP-Signaling Proteins , Humans , Acyltransferases/metabolism , Acyltransferases/antagonists & inhibitors , Acyltransferases/chemistry , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Adaptor Proteins, Signal Transducing/chemistry , Allosteric Regulation/drug effects , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/antagonists & inhibitors , DNA-Binding Proteins/chemistry , Protein Binding , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , TEA Domain Transcription Factors/chemistry , TEA Domain Transcription Factors/metabolism , Trans-Activators/metabolism , Trans-Activators/chemistry , Trans-Activators/antagonists & inhibitors , Transcription Factors/metabolism , Transcription Factors/antagonists & inhibitors , Transcription Factors/chemistry , Transcriptional Coactivator with PDZ-Binding Motif Proteins/chemistry , Transcriptional Coactivator with PDZ-Binding Motif Proteins/metabolism , YAP-Signaling Proteins/chemistry , YAP-Signaling Proteins/metabolismABSTRACT
The Hippo pathway is an evolutionarily conserved signaling pathway that plays critical roles in the tumorigenesis and progression of breast cancer, oral cancer, rectal cancer, colloid cancer, and so on. YAP/TAZ-TEAD complex is a key knot in the Hippo pathway regulating cell proliferation and stem cell functions. Activation or overexpression of this complex has been proved to lead to cell transformation, proliferation and eventually cancerization. In this review, the association between the alterations of hippo pathway and tumorigenesis of various cancer had been elucidated. The structural basis of YAP/TAZ-TEAD complex is analyzed, and the targeting inhibitors are summarized within the medicinal chemistry classification. Moreover, we have also discussed the clinical status and current challenges of these drug candidates, and provide guidance for the future development of inhibitors targeting this pathway, especially YAP/TAZ-TEAD complex.
