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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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Related in: MedlinePlus

Figure 1. Domain architecture of TEAD and its coactivators. (A) TEADs have a N-terminal TEA domain that binds DNA and a C-terminal transactivation domain that binds coactivators. YAP and TAZ have N-terminal TEAD-binding motif, one or two WW domains, which is followed by an activation domain. In Vgll proteins, the only recognizable feature is the Vestigial (Vg) motif and Vgll4 unlike other Vgll proteins, has two Vg motifs. Vg motif facilitates interaction with TEAD. Domain architecture of SRC1, a p160 coactivator, is shown. It interacts with TEAD through its N-terminal bHLH-PAS domain and it interacts with nuclear receptors through its NID (nuclear receptor interacting domain). In the C-terminus p160 has two activation domains. Ribbon diagram representation of TEA (B) and transactivation (C) domains of TEAD are shown. TEA domain adopts a homeodomain fold and the transactivation domain adopts an immunoglobulin-like β- sandwich fold.
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Figure 1: Figure 1. Domain architecture of TEAD and its coactivators. (A) TEADs have a N-terminal TEA domain that binds DNA and a C-terminal transactivation domain that binds coactivators. YAP and TAZ have N-terminal TEAD-binding motif, one or two WW domains, which is followed by an activation domain. In Vgll proteins, the only recognizable feature is the Vestigial (Vg) motif and Vgll4 unlike other Vgll proteins, has two Vg motifs. Vg motif facilitates interaction with TEAD. Domain architecture of SRC1, a p160 coactivator, is shown. It interacts with TEAD through its N-terminal bHLH-PAS domain and it interacts with nuclear receptors through its NID (nuclear receptor interacting domain). In the C-terminus p160 has two activation domains. Ribbon diagram representation of TEA (B) and transactivation (C) domains of TEAD are shown. TEA domain adopts a homeodomain fold and the transactivation domain adopts an immunoglobulin-like β- sandwich fold.

Mentions: All the four TEAD genes have the same domain architecture (Fig. 1). In the N-terminus, there is a DNA-binding TEA/ATTS domain that adopts a homeodomain fold (Fig. 1B).11 Biochemical and functional studies have revealed that TEA domain binds DNA elements such as 5′-GGAATG-3′ and this element is seen in the SV40 enhancer and in the promoter regions of TEAD target genes.1,11-13 The C-terminal region of TEAD adopts an immunoglobulin-like β-sandwich fold (Fig. 1C).14 This domain recruits transcription coactivators and therefore could be considered as a “transactivation” domain. TEAD on its own is unable to induce gene expression and it was already deduced from initial studies that TEADs require additional factors or coactivators for gene expression.15 Coactivators do not bind DNA; they pair with transcription factors and activate transcription. Coactivators generally have activation domains that facilitate their interaction with the basal transcription or chromatin remodeling machinery. Basal transcription machinery is a set of proteins that are required for the transcription of all genes, whereas the chromatin remodeling machinery decondenses the chromatin and makes it more conducive for the initiation of transcription. Several TEAD interacting coactivators have been identified and they can be classified into three broad groups: (1) YAP and its paralog TAZ; (2) Vgll proteins; and (3) p160 family of nuclear receptor coactivators. Activation domains are seen in YAP/TAZ16 and p160.17 The activation domain in YAP and TAZ may potentially bridge them with the basal transcription and chromatin remodelling machinery in order to activate transcription whereas the activation domains of p160 is shown to recruit proteins that facilitate chromatin remodeling. Vgll proteins on the other hand do not appear to have any activation domains and the molecular mechanism as to how they activate transcription is not known.


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

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

Figure 1. Domain architecture of TEAD and its coactivators. (A) TEADs have a N-terminal TEA domain that binds DNA and a C-terminal transactivation domain that binds coactivators. YAP and TAZ have N-terminal TEAD-binding motif, one or two WW domains, which is followed by an activation domain. In Vgll proteins, the only recognizable feature is the Vestigial (Vg) motif and Vgll4 unlike other Vgll proteins, has two Vg motifs. Vg motif facilitates interaction with TEAD. Domain architecture of SRC1, a p160 coactivator, is shown. It interacts with TEAD through its N-terminal bHLH-PAS domain and it interacts with nuclear receptors through its NID (nuclear receptor interacting domain). In the C-terminus p160 has two activation domains. Ribbon diagram representation of TEA (B) and transactivation (C) domains of TEAD are shown. TEA domain adopts a homeodomain fold and the transactivation domain adopts an immunoglobulin-like β- sandwich fold.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3672182&req=5

Figure 1: Figure 1. Domain architecture of TEAD and its coactivators. (A) TEADs have a N-terminal TEA domain that binds DNA and a C-terminal transactivation domain that binds coactivators. YAP and TAZ have N-terminal TEAD-binding motif, one or two WW domains, which is followed by an activation domain. In Vgll proteins, the only recognizable feature is the Vestigial (Vg) motif and Vgll4 unlike other Vgll proteins, has two Vg motifs. Vg motif facilitates interaction with TEAD. Domain architecture of SRC1, a p160 coactivator, is shown. It interacts with TEAD through its N-terminal bHLH-PAS domain and it interacts with nuclear receptors through its NID (nuclear receptor interacting domain). In the C-terminus p160 has two activation domains. Ribbon diagram representation of TEA (B) and transactivation (C) domains of TEAD are shown. TEA domain adopts a homeodomain fold and the transactivation domain adopts an immunoglobulin-like β- sandwich fold.
Mentions: All the four TEAD genes have the same domain architecture (Fig. 1). In the N-terminus, there is a DNA-binding TEA/ATTS domain that adopts a homeodomain fold (Fig. 1B).11 Biochemical and functional studies have revealed that TEA domain binds DNA elements such as 5′-GGAATG-3′ and this element is seen in the SV40 enhancer and in the promoter regions of TEAD target genes.1,11-13 The C-terminal region of TEAD adopts an immunoglobulin-like β-sandwich fold (Fig. 1C).14 This domain recruits transcription coactivators and therefore could be considered as a “transactivation” domain. TEAD on its own is unable to induce gene expression and it was already deduced from initial studies that TEADs require additional factors or coactivators for gene expression.15 Coactivators do not bind DNA; they pair with transcription factors and activate transcription. Coactivators generally have activation domains that facilitate their interaction with the basal transcription or chromatin remodeling machinery. Basal transcription machinery is a set of proteins that are required for the transcription of all genes, whereas the chromatin remodeling machinery decondenses the chromatin and makes it more conducive for the initiation of transcription. Several TEAD interacting coactivators have been identified and they can be classified into three broad groups: (1) YAP and its paralog TAZ; (2) Vgll proteins; and (3) p160 family of nuclear receptor coactivators. Activation domains are seen in YAP/TAZ16 and p160.17 The activation domain in YAP and TAZ may potentially bridge them with the basal transcription and chromatin remodelling machinery in order to activate transcription whereas the activation domains of p160 is shown to recruit proteins that facilitate chromatin remodeling. Vgll proteins on the other hand do not appear to have any activation domains and the molecular mechanism as to how they activate transcription is not known.

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