Monday, March 31, 2025
3/31/2025
Novel regulation and functions of TEAD-VGLL complex - Abstract TEAD transcription factors bind to the transcription co-activators YAP/TAZ, and control the transcriptional output of the Hippo pathway. In addition, TEADs could bind to Vestigial-like family proteins (VGLL1-4), regulating distinct transcription programs. Among all VGLL family proteins, VGLL3 has been shown to play critical roles in development, immune regulation and tumorigenesis. However, the detailed mechanisms and functions of TEAD-VGLL complex remains unclear. Here we identified TEAD binds to VGLL with distinct structural features, and alternative activation of TEAD-VGLL3 complex confers resistance to TEAD inhibitors (TEADi). We identified a new class of TEAD inhibitors, which could effectively block TEAD-VGLL3 complex, offering new structural and pharmacological insights to target TEAD-VGLL3 in signaling and diseases. Our specific aims of this proposal include: (1) To characterize the structure and functions of TEAD-Vgll3 complex. (2) To investigate the functions of TEAD-Vgll3 in TEADi resistance (3) To develop new generation of TEAD inhibitors blocking TEAD-Vgll3 complex.
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