Transcriptional enhancer factor TEF-1 also known as TEA domain family member 1 (TEAD1) and transcription factor 13 (TCF-13) is a protein that in humans is encoded by the TEAD1 gene. [5] [6] [7] [8] TEAD1 was the first member of the TEAD family of transcription factors to be identified. [5] [9]
All members of the TEAD family share a highly conserved DNA binding domain called the TEA domain. [10] This DNA binding domain has a consensus DNA sequence 5’-CATTCCA/T-3’ that is called the MCAT element. [11] The three dimensional structure of the TEA domain has been identified. [9] Its conformation is close to that of the homeodomain and contains 3 α helixes (H1, H2 and H3). It is the H3 helix that enables TEAD proteins to bind DNA. [12]
Another conserved domain of TEAD1 is located at the C terminus of the protein. It allows the binding of cofactors and has been called the YAP1 binding domain, because it is its ability to bind this well-known TEAD proteins co-factor that led to its identification. Indeed, TEAD proteins cannot induce gene expression on their own. They have to associate with cofactors to be able to act [13]
TEAD1 is expressed in various tissues including skeletal muscle, pancreas, placenta, lung, and heart. [14] [15] [16] [17] [18] [19] [20]
TEAD proteins are found in many organisms under different names, assuming different functions. For example, in Saccharomyces cerevisiae TEC-1 regulates the transposable element TY1 and is involved in pseudohyphale growth (the elongated shape that yeasts take when grown in nutrient-poor conditions). [21] In Aspergillus nidulans , the TEA domain protein ABAA regulates the differentiation of conidiophores. [22] In drosophila the transcription factor Scalloped is involved in the development of the wing disc, survival and cell growth. [23] Finally in Xenopus it has been demonstrated that the ortholog of TEAD1 regulates muscle differentiation. [24]
Protein Kinase A (pKA) can phosphorylate TEAD1 at serine 102, after the TEA domain. This phosphorylation is needed for the transcriptional activation of the α MyHC gene. [36] Protein Kinase C (pKC) phosphorylates TEAD1 on serine and threonine next to the last alpha loop in the TEA domain. This phosphorylation decreases TEAD1 binding to the GTIIC enhancer. [37] TEAD1 can be palmitoylated on a conserved cysteine at the C-term of the protein. This post-translational modification is critical for proper folding of TEAD proteins and their stability. [38]
TEAD proteins require cofactors to induce the transcription of target genes. [14] TEAD1 interacts with all members of the SRC family of steroid receptor coactivators. In HeLa cells TEAD1 and SRC induce gene expression, [39] TEAD1 interacts with PARP (poly (ADP-ribose) polymerase) to regulate smooth muscle α-actin expression. PARP can also ADP-ribosylate the TEAD proteins and make the chromatin context favorable to transcription through histone modification, [40] SRF (Serum response factor) and TEAD1 together regulate gene expression. [41]
TEAD proteins and MEF2 (myocyte enhancer factor 2) interact physically. The binding of MEF2 on DNA induces and potentiates TEAD1 recruitment at MCAT sequences that are adjacent to MEF2 binding sites. This recruitment leads to the repression of the MLC2v (Myosin Light Chain 2 v) and βMHC ( β-myosin heavy chain ) promoter. [42] TEAD1 and the phosphoprotein MAX interact in vivo and in vitro. Once this complex is formed, these two proteins can regulate the alpha-myosin heavy chain (α-MHC) gene expression. [43]
The four Vestigial-like (VGLL) proteins are able to interact with all TEADs. [44] The precise function of TEAD and VGLL interaction is still poorly understood. It has been shown that TEAD/VGLL1 complexes promote anchorage-independent cell proliferation in prostate cancer cell lines suggesting a role in cancer progression [45] Moreover, VGLL2 interaction with TEAD1 activates muscle promoter upon C2C12 differentiation and enhances MyoD-mediated myogenic in 10T1/2. [46] Finally the complex TEAD/VGLL4 acts as a default transcriptional repressor. [47]
The interaction between YAP (Yes Associated Protein 65), TAZ, a transcriptional coactivator paralog to YAP, and all TEAD proteins was demonstrated both in vitro and in vivo. In both cases the interaction of the proteins leads to increased TEAD transcriptional activity. [47] [48] YAP/TAZ are effectors of the Hippo tumor suppressor pathway that restricts organ growth by keeping in check cell proliferation and promoting apoptosis in mammals and also in Drosophila. [31] [49]
Analysis of cancer transcriptome databases (www.ebi.ac.uk/gxa) showed that TEAD1 is dysregulated in several types of cancers. First in Kaposi sarcoma there is a 300-fold increase in TEAD1 levels. Moreover, the increase of TEAD expression can be detected in basal-like breast cancers, [50] [51] fallopian tube carcinoma, [52] and germ cell tumors. [53] Otherwise, in other types of cancer TEAD expression is decreased, for example in other breast cancer types and in renal or bladder cancers. This dual role can be explained by the different targets and the differential regulation of target genes by TEAD transcription factors. [35] [54] Finally recent studies showed that TEAD1 and YAP in ovarian cancer can induces cell stemness and chemoresistance. [55] and that genetic variant of TEAD protein and YAP are enriched in some cancers. [56]
 | The 2016 version of this article was updated by an external expert under a dual publication model. The corresponding academic peer reviewed article was published in Gene and can be cited as: André Landin-Malt; Ataaillah Benhaddou; Alain Zider; Domenico Flagiello (14 July 2016). "An evolutionary, structural and functional overview of the mammalian TEAD1 and TEAD2 transcription factors". Gene . Gene Wiki Review Series. 591 (1): 292–303. doi:10.1016/J.GENE.2016.07.028. ISSN 0378-1119. PMC 7034536 . PMID 27421669. Wikidata Q30276357. |
MyoD, also known as myoblast determination protein 1, is a protein in animals that plays a major role in regulating muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub, belongs to a family of proteins known as myogenic regulatory factors (MRFs). These bHLH transcription factors act sequentially in myogenic differentiation. Vertebrate MRF family members include MyoD1, Myf5, myogenin, and MRF4 (Myf6). In non-vertebrate animals, a single MyoD protein is typically found.
An E-box is a DNA response element found in some eukaryotes that acts as a protein-binding site and has been found to regulate gene expression in neurons, muscles, and other tissues. Its specific DNA sequence, CANNTG, with a palindromic canonical sequence of CACGTG, is recognized and bound by transcription factors to initiate gene transcription. Once the transcription factors bind to the promoters through the E-box, other enzymes can bind to the promoter and facilitate transcription from DNA to mRNA.
In the field of molecular biology, myocyte enhancer factor-2 (Mef2) proteins are a family of transcription factors which through control of gene expression are important regulators of cellular differentiation and consequently play a critical role in embryonic development. In adult organisms, Mef2 proteins mediate the stress response in some tissues. Mef2 proteins contain both MADS-box and Mef2 DNA-binding domains.
TEAD2, together with TEAD1, defines a novel family of transcription factors, the TEAD family, highly conserved through evolution. TEAD proteins were notably found in Drosophila (Scalloped), C. elegans, S. cerevisiae and A. nidulans. TEAD2 has been less studied than TEAD1 but a few studies revealed its role during development.
CCAAT/enhancer-binding protein beta is a protein that in humans is encoded by the CEBPB gene.
Nuclear factor of activated T-cells, cytoplasmic 2 is a protein that in humans is encoded by the NFATC2 gene.
Myocyte-specific enhancer factor 2C also known as MADS box transcription enhancer factor 2, polypeptide C is a protein that in humans is encoded by the MEF2C gene. MEF2C is a transcription factor in the Mef2 family.
Activating transcription factor 4 , also known as ATF4, is a protein that in humans is encoded by the ATF4 gene.
Y box binding protein 1 also known as Y-box transcription factor or nuclease-sensitive element-binding protein 1 is a protein that in humans is encoded by the YBX1 gene. YBX1 is an RNA binding protein that stabilises messenger RNAs modified with N6-methyladenosine.
Myocyte-specific enhancer factor 2A is a protein that in humans is encoded by the MEF2A gene. MEF2A is a transcription factor in the Mef2 family. In humans it is located on chromosome 15q26. Certain mutations in MEF2A cause an autosomal dominant form of coronary artery disease and myocardial infarction.
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Myocyte-specific enhancer factor 2D is a protein that in humans is encoded by the MEF2D gene.
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Myocyte enhancer binding factor 2B (MEF2B) is a transcription factor part of the MEF2 gene family including MEF2A, MEF2C, and MEF2D. However, MEF2B is distant from the other three branches of MEF2 genes as it lacks the protein-coding Holliday junction recognition protein C-terminal (HJURP_C) region in vertebrates.
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