Structural insights into the YAP and TEAD complex

Abstract

The Yes-associated protein (YAP) transcriptional coactivator is a key regulator of organ size and a candidate human oncogene inhibited by the Hippo tumor suppressor pathway. The TEAD family of transcription factors binds directly to and mediates YAP-induced gene expression. Here we report the three-dimensional structure of the YAP (residues 50-171)-TEAD1 (residues 194-411) complex, in which YAP wraps around the globular structure of TEAD1 and forms extensive interactions via three highly conserved interfaces. Interface 3, including YAP residues 86-100, is most critical for complex formation. Our study reveals the biochemical nature of the YAP-TEAD interaction, and provides a basis for pharmacological intervention of YAP-TEAD hyperactivation in human diseases. The Yes-associated protein (YAP) is a transcriptional coactivator (Yagi et al. 1999). YAP knockout in mice causes embryonic lethality (Morin-Kensicki et al. 2006), indicating its critical role in development. In contrast, transgenic expression of YAP dramatically increases mouse liver size in a reversible fashion (Camargo et al. 2007;Dong et al. 2007), suggesting a key role of YAP in organ size regulation. Consistent with its growth-promoting function, yap genomic amplification and elevated protein levels have been observed in several human cancers (Overholtzer et al. 2006;Zender et al. 2006;Dong et al. 2007;Zhao et al. 2007;Steinhardt et al. 2008). Furthermore, expression of active YAP potently induces transformation in both NIH3T3 and MCF10A cells (Overholtzer et al. 2006;Zhao et al. 2009), and liver-specific transgenic expression of YAP causes tumor formation in vivo (Camargo et al. 2007;Dong et al. 2007). These observations support the function of YAP as a human oncogene.As a transcriptional coactivator, YAP needs to bind transcription factors to stimulate gene expression. Reported YAP target transcription factors include TEAD, p73, Runx2, and the ErbB4 cytoplasmic domain (Yagi et al. 1999;Strano et al. 2001;Vassilev et al. 2001;Komuro et al. 2003). However, only TEAD has been demonstrated to be important for the growth-promoting function of YAP Zhao et al. 2008). In humans, the TEAD family has four highly homologous proteins sharing a conserved DNA-binding TEA domain. YAP and TEAD1 bind to a common set of promoters in MCF10A cells (Zhao et al. 2008). Knockdown of TEAD aborts expression of the majority of YAP-inducible genes and largely attenuates YAP-induced overgrowth, epithelial-mesenchymal transition (EMT), and oncogenic transformation (Zhao et al. 2008). Furthermore, the phenotype of TEAD1/TEAD2 double-knockout mice resembles YAP knockout mice . Notably, the role of the YAP and TEAD complex in growth promotion is implicated in Sveinsson's chorioretinal atrophy caused by the TEAD1 Y406H mutation, which abolishes its interaction with and activation by YAP (Kitagawa 2007;Zhao et al. 2008). Consistently, Scalloped (Sd), the Drosophila homolog of TEAD, directly mediates Yorkie (Yki)-induced gene expression and overgrowth phenotypes (Zhao et al. 2007;Gou...

Discovery of recurrent structural variants in nasopharyngeal carcinoma

“…The target specificity may be provided by the YAP1 portion of the fusion (Fig. 4A), which contains a domain that interacts with the pluripotency transcription factor TEAD1 (Li et al 2010). In particular, the YAP1-TEAD1 complex was demonstrated to bind promoters of many genes important for ES cells, which are also targets of polycomb group proteins, NANOG, POU5F1, and SOX2 (Lian et al 2010).…”

Yap1 is dispensable for self‐renewal but required for proper differentiation of mouse embryonic stem ( ES ) cells

“…Additionally, the levels of pluripotency markers, such as Pou5f1 and Nanog, as well as various lineage markers were not significantly affected by either single or double KD of Yap1 and Taz (Fig 2C and D), indicating that the dispensability of Yap1 in self-renewing ES cells is not due to the compensatory effect of Taz. Since Yap1 is known to require Tead family proteins to activate its downstream target genes in NIH-3T3 and MCF10A cell lines [17,28,29], we investigated whether Tead proteins are also dispensable for the maintenance of ES cells. To do so, we first performed KD of Tead2 in ES cells.…”

“…A homologue of Yap1, Taz, shares redundant functions such as controlling cell proliferation and sensing mechanical stress [14,15]. Furthermore, Tead proteins-important in TE differentiation during early embryogenesis, form a complex with Yap1 and are known to activate their downstream target genes [16,17].…”

A novel partner of Scalloped regulates Hippo signaling via antagonizing Scalloped-Yorkie activity

“…The function of Sd-Yki complex has been intensively studied. In mammals, the structure and function of TEAD-YAP were well characterized [26][27][28]. Recent studies revealed that mammalian TEAD proteins are involved in the regulation of cell proliferation by cooperating with YAP under the control of Hpo signaling [29][30][31][32].…”