Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Tead

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_357

Synonyms

Historical Background

In vertebrates, the TEAD family of transcription factors is comprised of four members that contain a highly conserved (99–100%) DNA-binding domain, designated the TEA/ATTS domain (Burglin 1991) (Fig. 1). This highly conserved domain is comprised of three α helical domains and is not confined to vertebrates, but is also found in transcription factors from multiple organisms, including the TEAD1 homologs AbaA (Aspergillus nidulans), TEC1 (Saccharomyces cerevisiae), and scalloped (sd, Drosophila melanogaster). Thus TEAD family members represent primordial transcription factors, emphasizing their very early evolutionary origins and central importance in regulating gene expression and essential developmental functions. TEAD1 was originally cloned as a transcriptional enhancer factor (TEF) that was involved in mediating the activity of the Simian virus 40 (SV40) enhancer (Xiao et al. 1991). Subsequent studies revealed that TEAD family members bind to the MCAT motif, 5′-CATTCCT-3′, that is found in the promoter–enhancer regions of cardiac, smooth, and skeletal muscle-specific genes (reviewed in Yoshida 2008). In addition, TEAD family members have been found to be involved in the regulation of a diverse array of genes, including the human papilloma virus (HPV) E6 and E7 oncogenes, and human chorionic somatomammotropin, Foxa2, and PAX3 genes (reviewed in Eberhardt et al. 1996; Jacquemin and Davidson 1997; Kaneko and DePamphilis 1998; and Walker et al. 1991). Most knowledge of TEAD regulation of gene expression is derived from studies of muscle-specific genes.
Tead, Fig. 1

Schematic structure of TEAD family members showing the domains with enriched amino acids, serine (S), proline (P), hydrophobic, and hydroxylated (OH) and their relative degree of conservation. The N-terminal serine-rich domain is frequently phosphorylated, providing a mechanism for modulation of TEAD activity. The amino acid sequences of the highly conserved TEA DNA-binding domains (DBD) of TEAD1, AbaA (Aspergillus nidulans), TEC1 (Saccharomyces cerevisiae), and scalloped (SD, Drosophila melanogaster) and the α-helical regions are shown. The YAP/TAZ binding domain is indicated. The x-ray crystal structure of the YAP-TEAD4 complex indicates that the N-terminal region of YAP is folded into two short helices interspersed with a loop containing the PXXΦP motif and the C-terminal domain of TEAD4 has an immunoglobulin-like fold (Chen et al. 2010). The TEAD4-YAP binding is mediated chiefly by the two a-helices on the N-terminus of YAP. Numbers indicate amino acid positions for TEAD1 and are very similar for the other TEAD family members

TEAD genes play critical roles in mammalian development as demonstrated by knockout of the TEAD1 and TEAD4 genes, both of which lead to embryonic lethal phenotypes (Chen et al. 1994; Yagi et al. 2007). In addition, dual knockout of TEAD1 and TEAD2 results in embryonic lethality with severe growth defects and morphological abnormalities (Sawada et al. 2008), emphasizing the diverse critical roles TEAD family members play in mammalian development.

TEAD1

The human TEAD1 gene is located on chromosome 11p15.4. TEAD1, the prototypical member of the TEA/ATTS transcription factor family, is widely expressed in multiple tissues, including skeletal muscle, pancreas, placenta, lung, and heart. TEAD3 and TEAD4 share a similar tissue distribution, suggesting that these proteins have partially redundant functional roles. TEAD1 regulates the expression of several muscle-specific genes, including cardiac troponin T, ß-myosin heavy chain, smooth muscle α-actin, skeletal α-actin, and the α1-adrenergic receptor gene in cardiac myocytes (reviewed in Yoshida 2008). In addition, the expression of myocardin, the transcriptional co-activator of serum response factor (SRF), is regulated by an enhancer that is mediated by the combined actions of TEAD1, Mef2, and Foxo transcription factors. TEAD1 is required specifically for myocardin enhancer activation in neural-crest-derived smooth muscle cells and dorsal aorta. TEAD1 represses expression of the gene encoding involucrin in keratinocyte terminal differentiation and regulates early gene expression in mouse embryogenesis. TEAD1 has been implicated in the control of a placental enhancer/silencer driving the expression of the placental lactogens in syncytiotrophoblasts and inhibiting the expression of these genes in pituitary somatolactotrophs (reviewed in Eberhardt et al. 1996; Jacquemin and Davidson 1997; and Walker et al. 1991).

The most compelling evidence for TEAD1 involvement in cardiac development comes from studies of TEAD1 knockout mice, resulting in multiple cardiac defects and embryonic lethality (Chen et al. 1994). The mutant embryos exhibited enlarged pericardial cavity, bradycardia, a dilated fourth brain ventricle, and lethality at days e11.5–12.5. Heart development in the mutant embryos was extensive, indicating that TEAD1 was not required for initiation of heart development, but exhibited a very thin ventricular wall and reduced trabeculation. Transcription of several muscle-specific genes believed to be TEF-1 targets appeared to be normal, suggesting that many of these genes may be regulated by the other TEAD family members. The defect in cardiogenesis has been attributed to diminished transcription of one or several cardiac-specific genes that may be more specifically regulated by TEAD1.

TEAD2

The human TEAD2 gene is located on chromosome 19q13.3. The tissue-specific expression pattern of TEAD2 is unique, since it is essentially absent from adult tissues. TEAD2 is expressed during the first 7 days of embryonic development in selected embryonic tissues, including the cerebellum, testis, tail bud, and distal portion of the forelimb and hindlimb buds. TEAD2 is involved in mouse early embryo development and has been implicated along with Ets-1 in the regulation of CTP:phosphocholine cytidylyltransferase activity. Mouse TEAD2 has also been shown to be a regulator of Pax3, a transcription factor that is essential for premigratory neural-crest cells that give rise to the peripheral nervous system, melanocytes, and certain vascular smooth muscle cells. TEAD2 has also been shown to be important in effective muscle regeneration, where it acts in conjunction with MyoD and Fgfr4.

TEAD2 and TEAD1 have been shown to exhibit partially overlapping and redundant functions and are critical for normal development (Sawada et al. 2008). While mice lacking TEAD2 appear to be normal, knock out of both TEAD1 and TEAD2 genes results in an embryonic lethal phenotype at E9.5. Embryos exhibited reduced cell proliferation and increased apoptosis along with multiple severe growth defects and morphological abnormalities, including absence of a closed neural tube, notochord, and somites.

TEAD3

The human TEAD3 gene is located on chromosome 6p21.2. TEAD3 is expressed primarily in the heart and placenta. TEAD3 binds to the chorionic somatomammotropin gene enhancer and positively regulates hCS gene expression in human and murine placental cells (reviewed in Eberhardt et al. 1996; Jacquemin and Davidson 1997; and Walker et al. 1991). TEAD3 has also been implicated in the regulation of the gene encoding 3ß-hydroxysteroid dehydrogenase/isomerase in the placenta. In the heart TEAD3, along with TEAD4, is involved in regulating the expression of muscle-specific genes and is involved in mediating the α1-adrenergic response in cardiac myocytes.

TEAD4

The human TEAD4 gene is located on chromosome 12p13.2-p13.3. TEAD4 is expressed primarily in cardiac and skeletal muscle, where the protein activates muscle-specific genes through interactions with the muscle-specific MCAT response element. Genes regulated by TEAD4 include cardiac α-myosin heavy chain, skeletal muscle α -actin, and the S100B gene. TEAD4 seems to have a unique function in mediating the α1-adrenergic response in hypertrophic cardiac myocytes. The α1-adrenergic activation of TEAD4 appears to require phosphorylation at Ser 322. TEAD4 has also been implicated in the regulation of vascular endothelial growth factor (VEGF) in the ischemic heart and hypoxic endothelial cells.

Knock out of the mouse TEAD4 gene in mice results in a preimplantation lethal phenotype (Yagi et al. 2007). Specification of mammalian cell lineages begins shortly after fertilization with formation of a blastocyst comprised of trophectoderm and inner cell mass (ICM), giving rise to the placenta and embryo, respectively. TEAD4(−/−) embryos lack expression of trophectoderm-specific genes, including Cdx2, and lack trophoblast stem cells, trophectoderm, or blastocoel cavities with resultant inability to implant into the uterine endometrium. However, conditional knock out of TEAD4 embryos after implantation results in complete development, demonstrating that TEAD4 is the earliest gene required for specification of the trophectoderm lineage.

Co-regulatory Molecules Involved in TEAD Function

Like most transcription factors, the TEAD family interacts with a number of co-activator molecules that are essential for TEAD function. Two well-studied interactions include the vestigial and Yki/Yap/Taz family of proteins (Fig. 2). In Drosophila, the TEAD1 homolog Scalloped (Sd) interacts with Vestigial (Vg) to form a complex that binds DNA through the TEA/ATTS DNA-binding domain of Sd. The Sd–Vg complex is a critical regulator of wing development. In humans, there is a family of vestigial-related (Vgl) gene products, which interact with TEAD1. Vgl-2 (VITO-1), a member of the SID or scalloped interaction domain-containing gene products, interacts with TEAD1 and is associated with differentiation during embryonic skeletal myogenesis. Vgl-4, a novel member of the vestigial-like family of transcription cofactors, regulates α1-adrenergic activation of gene expression in cardiac myocytes.
Tead, Fig. 2

Schematic diagram of known components of regulation of TEAD activity and interaction with other transcriptional control elements in the regulation of mammalian gene expression. Within the nucleus, TEAD family members interact with a number of transcription factors indicated by double-headed arrows. The indicated pathways emphasize the regulation of muscle-specific genes (Yoshida 2008). Not all interactions are implied to occur simultaneously. Localization of YAP/TAZ within the nucleus is mediated by members of the Hippo intracellular kinase signaling cascade (Zhao et al. 2008). Members of the Hippo pathway in mammals include the hippo (Hpo) homolog Mst (Mst1/2, or STK4/STK3), the Sav homolog WW45, the Mats homolog Mob, the Wts homolog Lats (Lats1/2), and the yorkie (Yki) homologs YAP and TAZ

Recent studies have implicated the Hippo signaling pathway in the control of organ size and tumorigenesis in both Drosophila and mammals (reviewed in Zhao et al. 2008). The Hippo pathway modulates the nuclear localization of the paralogous Yki/YAP/TAZ transcription co-activators that interact directly with the TEAD family transcription factors. In mammalian cells, the Hippo pathway kinase cascade phosphorylates YAP and TAZ, which prevents their nuclear localization via an interaction with the 14-3-3 protein. All TEAD family members have been shown to bind YAP65, a powerful transcriptional co-activator. It has been suggested that YAP65 regulates TEAD-dependent transcription in response to mitogenic signals.

Several other proteins have been shown to interact with TEAD family members that are important in modulating TEAD function. TEAD1 interacts with poly(ADP-ribose) (PARP) polymerase and this interaction has been proposed to provide muscle-specific gene expression in cardiac myocytes. PARP is thought to be an auxiliary protein required for TEAD1 transcriptional function. TEAD1 interacts with the basic helix–loop–helix zipper protein Max. Max is thought to cooperate with TEAD1 to regulate expression of the gene encoding α-myosin heavy chain. Multiprotein complexes of TEAD1, Max, and PARP have been proposed to be involved in gene expression in slow muscle fibers. TEAD1 binds to the TATA-binding protein (TBP), resulting in the loss of the ability of TBP to bind to the TATA box, and may be partly responsible for TEAD1 transrepressor activity. TEAD1 has been shown to bind the SV40 large T antigen. TEAD1 interacts with SRF and Mef2 in cardiomyocytes. TEAD1 and TEAD2 have been shown to interact with  SRC1 and all members of the p160 family including SRC1, TIF2, and  RAC3, and all of these factors are able to potentiate transcription from a TEF response element in vitro.

Summary

The TEAD family of transcription factors evolved very early and plays critical roles in the regulation of gene expression in yeast, flies, plants, and mammals. TEAD function is critical for mammalian development, including cardiac, trophoblast, neural tube, notochord, and somite development. TEAD family members regulate the expression of a large variety of genes including viral, muscle-specific, and developmentally important genes such as Cdx2 and Pax3. Considerable insight into the mechanisms by which TEAD family members regulate gene expression has been obtained, including the interaction of a large number of other transcription factors and/or co-regulators, such as Max, Mef2, SRF, YAP/TAZ, and Vgl. Future studies are anticipated to uncover many additional developmental and regulatory pathways that are mediated by TEAD family members. In addition, increasing detail will be added at the molecular level to our understanding of the discrete mechanisms by which TEAD family members regulate gene expression.

Notes

Acknowledgments

I wish to extend my apologies to the many authors whose contributions could not be cited due to space limitations. Where possible I have cited review articles to allow readers access to the literature. In addition, the readers may access additional information and references on TEAD via the Nature-UCSD signaling gateway: http://www.signaling-gateway.org/.

References

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Departments of Medicine and Biochemistry and Molecular BiologyMayo ClinicRochesterUSA