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Emerging roles of TEAD transcription factors and its coactivators in cancers.

Pobbati AV, Hong W - Cancer Biol. Ther. (2013)

Bottom Line: They facilitate cancer progression through expression of proliferation promoting genes such as c-myc, survivin, Axl, CTGF and Cyr61.Given the fact that TEADs and their coactivators need to work together for a functional outcome, disrupting the interaction between them appears to be a viable option for cancer therapy.Structures of TEAD-coactivator complexes have been elucidated and will facilitate drug design and development.

View Article: PubMed Central - PubMed

Affiliation: Cell Biology in Health and Disease Division, Institute of Molecular and Cell Biology, Proteos, Singapore, Singapore. ajaybabuvp@imcb.a-star.edu.sg

ABSTRACT
TEAD proteins are transcription factors that are crucial for development, but also play a role in cancers. Several developmentally and pathologically important genes are upregulated by TEADs. TEADs have a TEA domain that enables them to bind specific DNA elements and a transactivation domain that enables them to interact with coactivators. TEADs on their own are unable to activate transcription and they require the help of coactivators. Several TEAD-interacting coactivators are known and they can be classified into three groups: (1) YAP and its paralog TAZ; (2) Vgll proteins; and (3) p160s. Accordingly, these coactivators also play a role in development and cancers. Recent studies have shown that TEADs and their coactivators aid in the progression of various cancers, including the difficult to treat glioblastoma, liver and ovarian cancers. They facilitate cancer progression through expression of proliferation promoting genes such as c-myc, survivin, Axl, CTGF and Cyr61. There is also a good correlation between high TEAD or its coactivator expression and poor prognosis in various cancers. Given the fact that TEADs and their coactivators need to work together for a functional outcome, disrupting the interaction between them appears to be a viable option for cancer therapy. Structures of TEAD-coactivator complexes have been elucidated and will facilitate drug design and development.

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Figure 2. Structures of YAP/Vgll1-TEAD core complexes. (A) The core complex structures have the transactivation domain of TEAD in complex with either the TEAD-interacting motif of YAP or the Vg motif of Vgll1. YAP interacts with TEAD by forming three interfaces and Vg motif interacts with TEAD by forming two interfaces. The interface 1 and 2 in both the complexes are strikingly similar. (B) A closer look at the interface 2 of Vgll1-TEAD complex. The surface of TEAD is shown as green mesh. Vgll1 helix binds to the hydrophobic groove in TEAD and the crucial region in Vgll1 is the V41xxH44 F45 motif. The side chains of these residues that are shown as pink spheres and they bind to the complementary pockets in TEAD. Similar interaction is also seen in YAP but it has LxxLF motif. (C) The amino acid sequence of the Vg motif of Vgll1 and the TEAD-binding motif of YAP. The LxxLF and the VxxHF motifs are shown in red.
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Figure 2: Figure 2. Structures of YAP/Vgll1-TEAD core complexes. (A) The core complex structures have the transactivation domain of TEAD in complex with either the TEAD-interacting motif of YAP or the Vg motif of Vgll1. YAP interacts with TEAD by forming three interfaces and Vg motif interacts with TEAD by forming two interfaces. The interface 1 and 2 in both the complexes are strikingly similar. (B) A closer look at the interface 2 of Vgll1-TEAD complex. The surface of TEAD is shown as green mesh. Vgll1 helix binds to the hydrophobic groove in TEAD and the crucial region in Vgll1 is the V41xxH44 F45 motif. The side chains of these residues that are shown as pink spheres and they bind to the complementary pockets in TEAD. Similar interaction is also seen in YAP but it has LxxLF motif. (C) The amino acid sequence of the Vg motif of Vgll1 and the TEAD-binding motif of YAP. The LxxLF and the VxxHF motifs are shown in red.

Mentions: Among the Vgll proteins, Vgll1, also called TONDU, was the first to be identified. In Drosophila, Vgll1 is able to partially rescue Vg loss of function phenotype.63 This is remarkable because other than the Vg motif there is no other sequence similarity between Vg and Vgll1. Interaction with TEAD is crucial for its function and Vgll1 is shown to interact with all four mammalian TEADs.63 In humans it is expressed in the fetal lung, heart, kidney and placenta. In Xenopus its expression is restricted to epidermal cells and the expression levels can be modulated by activin and BMP treatments.64 Vgll1 also promotes cell proliferation, similar to Vg or YAP/TAZ. Even the core complex structure of Vgll1-TEAD is similar to that of YAP-TEAD (Fig. 2A). Given the structural and functional similarity, we proposed that Vgll1 could also play a role in human cancers.65 There is evidence for Vgll1’s role in bladder cancer and its expression is used to classify tumors into good and bad prognosis groups.66 High Vgll1 levels are seen in basal-like breast cancers, but it is not known whether it contributes to cancer progression.22


Emerging roles of TEAD transcription factors and its coactivators in cancers.

Pobbati AV, Hong W - Cancer Biol. Ther. (2013)

Figure 2. Structures of YAP/Vgll1-TEAD core complexes. (A) The core complex structures have the transactivation domain of TEAD in complex with either the TEAD-interacting motif of YAP or the Vg motif of Vgll1. YAP interacts with TEAD by forming three interfaces and Vg motif interacts with TEAD by forming two interfaces. The interface 1 and 2 in both the complexes are strikingly similar. (B) A closer look at the interface 2 of Vgll1-TEAD complex. The surface of TEAD is shown as green mesh. Vgll1 helix binds to the hydrophobic groove in TEAD and the crucial region in Vgll1 is the V41xxH44 F45 motif. The side chains of these residues that are shown as pink spheres and they bind to the complementary pockets in TEAD. Similar interaction is also seen in YAP but it has LxxLF motif. (C) The amino acid sequence of the Vg motif of Vgll1 and the TEAD-binding motif of YAP. The LxxLF and the VxxHF motifs are shown in red.
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Related In: Results  -  Collection

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Figure 2: Figure 2. Structures of YAP/Vgll1-TEAD core complexes. (A) The core complex structures have the transactivation domain of TEAD in complex with either the TEAD-interacting motif of YAP or the Vg motif of Vgll1. YAP interacts with TEAD by forming three interfaces and Vg motif interacts with TEAD by forming two interfaces. The interface 1 and 2 in both the complexes are strikingly similar. (B) A closer look at the interface 2 of Vgll1-TEAD complex. The surface of TEAD is shown as green mesh. Vgll1 helix binds to the hydrophobic groove in TEAD and the crucial region in Vgll1 is the V41xxH44 F45 motif. The side chains of these residues that are shown as pink spheres and they bind to the complementary pockets in TEAD. Similar interaction is also seen in YAP but it has LxxLF motif. (C) The amino acid sequence of the Vg motif of Vgll1 and the TEAD-binding motif of YAP. The LxxLF and the VxxHF motifs are shown in red.
Mentions: Among the Vgll proteins, Vgll1, also called TONDU, was the first to be identified. In Drosophila, Vgll1 is able to partially rescue Vg loss of function phenotype.63 This is remarkable because other than the Vg motif there is no other sequence similarity between Vg and Vgll1. Interaction with TEAD is crucial for its function and Vgll1 is shown to interact with all four mammalian TEADs.63 In humans it is expressed in the fetal lung, heart, kidney and placenta. In Xenopus its expression is restricted to epidermal cells and the expression levels can be modulated by activin and BMP treatments.64 Vgll1 also promotes cell proliferation, similar to Vg or YAP/TAZ. Even the core complex structure of Vgll1-TEAD is similar to that of YAP-TEAD (Fig. 2A). Given the structural and functional similarity, we proposed that Vgll1 could also play a role in human cancers.65 There is evidence for Vgll1’s role in bladder cancer and its expression is used to classify tumors into good and bad prognosis groups.66 High Vgll1 levels are seen in basal-like breast cancers, but it is not known whether it contributes to cancer progression.22

Bottom Line: They facilitate cancer progression through expression of proliferation promoting genes such as c-myc, survivin, Axl, CTGF and Cyr61.Given the fact that TEADs and their coactivators need to work together for a functional outcome, disrupting the interaction between them appears to be a viable option for cancer therapy.Structures of TEAD-coactivator complexes have been elucidated and will facilitate drug design and development.

View Article: PubMed Central - PubMed

Affiliation: Cell Biology in Health and Disease Division, Institute of Molecular and Cell Biology, Proteos, Singapore, Singapore. ajaybabuvp@imcb.a-star.edu.sg

ABSTRACT
TEAD proteins are transcription factors that are crucial for development, but also play a role in cancers. Several developmentally and pathologically important genes are upregulated by TEADs. TEADs have a TEA domain that enables them to bind specific DNA elements and a transactivation domain that enables them to interact with coactivators. TEADs on their own are unable to activate transcription and they require the help of coactivators. Several TEAD-interacting coactivators are known and they can be classified into three groups: (1) YAP and its paralog TAZ; (2) Vgll proteins; and (3) p160s. Accordingly, these coactivators also play a role in development and cancers. Recent studies have shown that TEADs and their coactivators aid in the progression of various cancers, including the difficult to treat glioblastoma, liver and ovarian cancers. They facilitate cancer progression through expression of proliferation promoting genes such as c-myc, survivin, Axl, CTGF and Cyr61. There is also a good correlation between high TEAD or its coactivator expression and poor prognosis in various cancers. Given the fact that TEADs and their coactivators need to work together for a functional outcome, disrupting the interaction between them appears to be a viable option for cancer therapy. Structures of TEAD-coactivator complexes have been elucidated and will facilitate drug design and development.

Show MeSH
Related in: MedlinePlus