Abstract
The Hippo pathway is a tumor suppressor pathway that is implicated in the regulation of organ size. The pathway has three components: the upstream regulatory factors, the kinase core, and the downstream transcriptional machinery, which consists of YAP, TAZ (transcription co-activators) and TEAD (transcription factor). Formation of YAP/TAZ-TEAD complexes leads to the transcription of growth-promoting genes. Herein, we report the crystal structure of TAZ-TEAD4 complex, which reveals two binding modes. The first is similar to the published YAP-TEAD structure. The second is a unique binding mode, whereby two molecules of TAZ bind to and bridge two molecules of TEAD4. We validated the latter using cross-linking and multi-angle light scattering. Using siRNA, we showed that TAZ knockdown leads to a decrease in TEAD4 dimerization. Lastly, results from luciferase assays, using YAP/TAZ transfected or knockdown cells, give support to the non-redundancy of YAP/TAZ co-activators in regulating gene expression in the Hippo pathway.
Highlights
Mammalian homologues of the proteins in the Hippo pathway have been characterized and grouped into three components: the upstream regulatory factors involved in cell-to-cell signaling (FRMD6, NF2), the kinase core (MST, WW45, LATS, MOB1), and the downstream transcriptional machinery (YAP, TAZ, TEAD), which leads to the expression of genes involved in cell proliferation and anti-apoptosis
We report the crystal structure of mouse TAZ-TEAD4 complex, which reveals a distinct binding mode not observed in YAP-TEAD complex
The TAZ-TEAD complex crystallizes with four molecules of TAZ and four molecules of TEAD in the asymmetric unit
Summary
Mammalian homologues of the proteins in the Hippo pathway have been characterized and grouped into three components: the upstream regulatory factors involved in cell-to-cell signaling (FRMD6, NF2), the kinase core (MST, WW45, LATS, MOB1), and the downstream transcriptional machinery (YAP, TAZ, TEAD), which leads to the expression of genes involved in cell proliferation and anti-apoptosis. The overexpression of YAP and TAZ has been shown to promote cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), tumourigenesis and is linked to poor prognosis and decreased patient survival[7,8,9]. They play a key role in the regulation of stem cell self-renewal and may be a critical link between stem cells and cancer cells[10]. TAZ expression levels do not modulate YAP abundance, making it a uni-directional relationship between YAP and TAZ31
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
