TEAD
The four human TEAD proteins (TEAD1-4, formerly TEF-1, TEF-4, TEF-5 and TEF-3) bind the MCAT element GGAATG, read on the other strand as CATTCC. The DNA-binding TEA domain is a three-helix bundle with a homeodomain-like fold, and two TEADs load cooperatively onto tandem MCAT sites. TEADs have no activation domain of their own: they are the DNA-binding platform for the Hippo pathway coactivators YAP and TAZ, and for the VGLL proteins that compete with them. The motif is therefore the readout of Hippo signaling status on chromatin. TEAD sites drive muscle gene expression, trophectoderm specification and organ size control, and are central to YAP-driven cancers.
The factors
Four human genes, TEAD1, TEAD2, TEAD3 and TEAD4, share an N-terminal TEA (also called ATTS) DNA binding domain and a C-terminal YAP-binding domain. TEAD1 (TEF-1) and TEAD3 (TEF-5) are broadly expressed with enrichment in muscle and placenta, TEAD2 (TEF-4) in neural and embryonic tissue, TEAD4 (TEF-3) in skeletal muscle, trophectoderm and many carcinomas. TEADs bind DNA as monomers but load cooperatively onto tandem sites via a loop in the TEA domain 2843293,17085591. They carry no intrinsic transactivation domain, so their output depends entirely on which partner occupies the YAP-binding domain: YAP or TAZ (WWTR1) when Hippo signaling is off, or a VGLL protein (VGLL1-VGLL4) competing for the same surface 18579750,22632831. Structures of the YAP-TEAD, TAZ-TEAD and VGLL1-TEAD complexes show how the same interface is reused 20123905,22632831. TEADs are also palmitoylated on a conserved cysteine in a hydrophobic central pocket; this auto-palmitoylation is required for stability and for YAP/TAZ binding 26724994,31043565, and it is the target of the current generation of TEAD inhibitors 33850002.
The motif
The literature name is the MCAT (muscle CAT) element, GGAATG, equivalently CATTCC on the opposite strand 17962623; older papers also call it the GT-IIC element of the SV40 enhancer 2843293,1851669. TEF-1 was purified as a protein binding both GT-IIC and a second SV40 motif, Sph, but the two are unrelated in sequence, so Sph is not another name for the MCAT site 2843293. Six bases carry essentially all the information, with the GGAAT core most constrained. The solution structure of the TEA domain showed a three-helix bundle with a homeodomain fold, and revealed that the L1 loop is what allows two TEAD molecules to load cooperatively onto tandemly duplicated MCAT sites 17085591. That explains the pattern in this family's data: single-site models span 6-9 columns with 10-13 bits, while the most informative models (up to 21 bits) are tandem pairs such as CATTCC-N(2)-CATTCC, which represent the cooperative arrangement rather than a longer monomer footprint. Database models divide simply into the forward-strand rendering (GGAATG, GGAATGT) and the reverse rendering (ACATTCC, CATTCCA); they are the same motif and the family is one of the most cohesive in these collections. No TEAD paralogue is distinguishable from another by sequence. An in vitro microarray study also found that the isolated TEA domain binds a broader set of sequences than the sites recovered with the full-length protein, so the narrow GGAATG consensus partly reflects constraints outside the DNA-binding domain 17085591.
Where it acts
TEAD/YAP sites are overwhelmingly enhancer elements, not promoters. YAP-TEAD complexes occupy thousands of distal enhancers and act largely through enhancer-promoter contacts 26258633 and release of paused RNA polymerase; TEAD motifs are among the most enriched motifs in the accessible chromatin of proliferating and mechanically stimulated cells. The classic promoter-proximal cases are muscle: MCAT elements in the cardiac troponin T, beta-myosin heavy chain and smooth muscle alpha-actin promoters 17962623. Recurrent co-occurring motifs are AP-1 (JUN/FOS), which forms functional composite TEAD-AP-1 enhancers in many YAP-driven contexts 26258633, plus RUNX, MYOD E-boxes in muscle, and CDX2/GATA3 in trophectoderm. Because GGAATG is only 6 bp, chance matches are extremely numerous; occupancy is set by chromatin state and by whether YAP/TAZ are nuclear.
Biology and disease
TEAD4 specifies the trophectoderm lineage in the mouse preimplantation embryo 17913785, and its activity is restricted to outer cells by Hippo signaling through LATS and YAP 19289085, making this the earliest known cell-fate decision read out through a TEAD motif. In muscle, MCAT elements coordinate the cardiac and smooth muscle differentiation programs. A missense mutation in TEAD1 that weakens its interaction with YAP and TAZ causes Sveinsson chorioretinal atrophy, a dominant retinal degeneration 15016762,17689488, and is the clearest human germline TEAD disease. In cancer, TEAD activity is the effector of Hippo pathway loss: NF2 (merlin) inactivation in mesothelioma and schwannoma, LATS1/2 loss, and YAP1 or WWTR1 fusions all converge on TEAD-driven transcription, and YAP1-TFE3 and TAZ-CAMTA1 fusions in epithelioid hemangioendothelioma retain the TEAD-binding function. Small-molecule inhibitors of TEAD auto-palmitoylation selectively suppress NF2-deficient mesothelioma in preclinical models 33850002 and have entered clinical testing. VGLL4 acts as a tumor suppressor by competing with YAP for the same TEAD surface.
Reading a hit
GGAATG is 6 bp and occurs on the order of a million times in the human genome, so an isolated match is close to meaningless. Three things upgrade a hit: a tandem pair of MCAT sites within about 15 bp, which is the cooperative binding arrangement; an adjacent AP-1 site, which marks the functional TEAD-AP-1 composite enhancers; and open chromatin in a cell with nuclear YAP or TAZ. A hit never identifies a paralogue; TEAD1 through TEAD4 share one matrix, and in most tissues more than one is expressed. Equally important, a TEAD motif hit says nothing about the direction of the output, because the same site is bound by TEAD with YAP/TAZ (activating) or with VGLL4 (repressing), and TEAD occupancy in the absence of a coactivator does little. ChIP-derived TEAD motifs are reasonably trustworthy here: HOCOMOCO grade-A models for TEAD1-4 combine ChIP-seq with in vitro selection (evidence codes PS or PSM), so direct binding is independently supported. The converse caution applies to the reverse: YAP and TAZ ChIP-seq recovers the TEAD motif even though YAP and TAZ do not touch DNA 26258633, a textbook case of a coactivator "having" the motif of the protein that recruits it. If a database entry attributes GGAATG to YAP1, WWTR1 or a VGLL protein, that is indirect binding.
How this was worked out
TEF-1 is purified from HeLa cells as a protein that binds two sequence-unrelated SV40 enhancer motifs, GT-IIC and Sph, and binds cooperatively to tandem but not inverted or spaced repeats, which correlates with enhancer activity.
Still open then: How one protein recognized two unrelated motifs.
Cloned TEF-1 is unrelated to known transcription factors and binds the GT-IIC and Sph enhansons, but its activation depends on a limiting, possibly cell-specific intermediary factor that it can squelch.
Still open then: The identity of the limiting coactivator.
The solution structure of the TEA domain is a three-helix bundle with a homeodomain fold; its L1 loop is needed for cooperative loading on tandem MCAT sites, and on microarrays the isolated domain binds a broader set of elements than the known full-length sites.
TEAD factors are required for YAP-dependent gene expression, growth, transformation and EMT, with CTGF as a direct target, and the YAP-TEAD relationship is conserved in Drosophila Yorkie and Scalloped, placing TEAD in the Hippo pathway.
- 2009highKnockout embryos, gain and loss of function in embryos and ES cells, protein localization17913785 19289085
TEAD4 is required to specify trophectoderm in the preimplantation mouse embryo, and Hippo signaling through LATS confines nuclear YAP, and so TEAD4 activity, to outer cells.
The YAP-TEAD1 structure shows YAP wrapping the globular TEAD YAP-binding domain through three interfaces; a 2012 VGLL1-TEAD4 structure shows VGLL1 using the same surface despite an unrelated sequence.
- 2015highChIP-seq, chromatin conformation, genetic gain and loss of function in cells and mice26258633
In breast cancer cells YAP/TAZ reach DNA through TEAD at composite elements carrying both TEAD and AP-1 motifs, almost exclusively at distal enhancers that loop to promoters; AP-1 loss blunts YAP/TAZ-driven growth.
- 2016highX-ray crystallography, biochemical palmitoylation assays, medicinal chemistry, xenografts26724994 33850002
TEADs are palmitoylated on a conserved cysteine with the lipid buried in a central hydrophobic pocket, and the modification is required for folding and stability; by 2021 small molecules blocking auto-palmitoylation selectively inhibit NF2-deficient mesothelioma.
Still unresolved
- Whether TEAD has a second binding specificity is unresolved: purified TEF-1 bound two SV40 motifs of unrelated sequence (GT-IIC and Sph) and the isolated TEA domain binds a broader set of elements on microarrays, yet every database model here reduces to the single GGAATG/CATTCC site.
- How much genomic TEAD binding uses the cooperative tandem arrangement is not established: the most informative in vitro models (HT-SELEX TEAD1 and TEAD3) are paired CATTCC sites, whereas the ChIP-supported models are single sites.
GGAATG carries about 6 bits, so single hits are expected by chance and are not evidence on their own; tandem MCAT pairs and neighboring AP-1 sites are what make a hit credible. TEAD1-4 share one matrix and cannot be separated by sequence. A hit does not indicate activation: the same site is used by TEAD-YAP/TAZ and by repressive TEAD-VGLL4 complexes, and TEAD without a coactivator is largely inert. Any GGAATG motif attributed to YAP1, WWTR1/TAZ or a VGLL protein is indirect, since those proteins do not contact DNA. TEAD's own models are supported by in vitro selection as well as ChIP-seq.
References
- Anbanandam A, Albarado DC, Nguyen CT, et al. Insights into transcription enhancer factor 1 (TEF-1) activity from the solution structure of the TEA domain. Proc Natl Acad Sci U S A 2006;103:17225-30. PMID 17085591
- Yoshida T. MCAT elements and the TEF-1 family of transcription factors in muscle development and disease. Arterioscler Thromb Vasc Biol 2008;28:8-17. PMID 17962623
- Li Z, Zhao B, Wang P, et al. Structural insights into the YAP and TEAD complex. Genes Dev 2010;24:235-40. PMID 20123905
- Pobbati AV, Chan SW, Lee I, et al. Structural and functional similarity between the Vgll1-TEAD and the YAP-TEAD complexes. Structure 2012;20:1135-40. PMID 22632831
- Noland CL, Gierke S, Schnier PD, et al. Palmitoylation of TEAD Transcription Factors Is Required for Their Stability and Function in Hippo Pathway Signaling. Structure 2016;24:179-186. PMID 26724994
- Tang TT, Konradi AW, Feng Y, et al. Small Molecule Inhibitors of TEAD Auto-palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2-deficient Mesothelioma. Mol Cancer Ther 2021;20:986-998. PMID 33850002
- Yagi R, Kohn MJ, Karavanova I, et al. Transcription factor TEAD4 specifies the trophectoderm lineage at the beginning of mammalian development. Development 2007;134:3827-36. PMID 17913785
- Nishioka N, Inoue K, Adachi K, et al. The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev Cell 2009;16:398-410. PMID 19289085
- Fossdal R, Jonasson F, Kristjansdottir GT, et al. A novel TEAD1 mutation is the causative allele in Sveinsson's chorioretinal atrophy (helicoid peripapillary chorioretinal degeneration). Hum Mol Genet 2004;13:975-81. PMID 15016762
- Kitagawa M. A Sveinsson's chorioretinal atrophy-associated missense mutation in mouse Tead1 affects its interaction with the co-factors YAP and TAZ. Biochem Biophys Res Commun 2007;361:1022-6. PMID 17689488
- Kim NG, Gumbiner BM. Cell contact and Nf2/Merlin-dependent regulation of TEAD palmitoylation and activity. Proc Natl Acad Sci U S A 2019;116:9877-9882. PMID 31043565
- Vierstra J, Lazar J, Sandstrom R, et al. Global reference mapping of human transcription factor footprints. Nature 2020;583:729-736. PMID 32728250
- Davidson I, Xiao JH, Rosales R, et al. The HeLa cell protein TEF-1 binds specifically and cooperatively to two SV40 enhancer motifs of unrelated sequence. Cell 1988;54:931-42. PMID 2843293
- Xiao JH, Davidson I, Matthes H, et al. Cloning, expression, and transcriptional properties of the human enhancer factor TEF-1. Cell 1991;65:551-68. PMID 1851669
- Zhao B, Ye X, Yu J, et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev 2008;22:1962-71. PMID 18579750
- Zanconato F, Forcato M, Battilana G, et al. Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat Cell Biol 2015;17:1218-27. PMID 26258633
17 motifs in this family — JASPAR 4 · HOCOMOCO 8 · CIS-BP 4 · Vierstra 1
| motif | database | consensus | bits |
|---|---|---|---|
| TEAD1.H14CORE.2.S.CSC | HOCOMOCO | aCATTCCtnaCATTCC | 21.3 |
| M03575_2.00 | CIS-BP | GGAATGcnaGGAATGt | 17.5 |
| TEAD3.H14CORE.1.S.BSB | HOCOMOCO | aCATTCCtngCATTCC | 15.7 |
| TEAD2.H14CORE.0.PSM.APSMA | HOCOMOCO | gCATTCCA | 13.5 |
| TEAD1.H14CORE.0.PSM.APSMA | HOCOMOCO | aCATTCCaG | 12.9 |
| TEAD4.H14CORE.1.P.BPB | HOCOMOCO | aCATTCCtGgcAT | 12.6 |
| TEAD1 (MA0090.4) | JASPAR | ACATTCCAG | 12.4 |
| TEAD3.H14CORE.0.PS.APSA | HOCOMOCO | aCATTCCaG | 12 |
| TEAD3 (MA0808.1) | JASPAR | aCATTCCa | 11.5 |
| TEAD1.H14CORE.1.P.CPC | HOCOMOCO | ACATTCCTngcAT | 11.5 |
| TEAD4 (MA0809.3) | JASPAR | ACATTCCA | 11.3 |
| TEAD4.H14CORE.0.PS.APSA | HOCOMOCO | aCATTCCt | 11.1 |
| M08175_2.00 | CIS-BP | GGAATGT | 11.1 |
| TEAD2 (MA1121.2) | JASPAR | ACATTCC | 10.5 |
| M05825_2.00 | CIS-BP | GGaATGc | 10.3 |
| M03579_2.00 | CIS-BP | GGAATGT | 9.4 |
| AC0652:TEAD:TEA | Vierstra | GGAATGt | 8.6 |
HOCOMOCO tags read as assay + quality grade: P ChIP-seq, S HT-SELEX, M methyl-HT-SELEX, G GHT-SELEX, I SMiLE-seq, B PBM; grade A means two or more assay types agreed. A P-only matrix is a record of where the protein was crosslinked, which need not be a sequence it binds itself.
The factors, elsewhere
These entries are written from the primary literature and every citation is checked against PubMed, but this one can still be out of date, too confident, or simply wrong — especially where a motif’s published site and its database matrices disagree. Corrections and additions are welcome, and they are the fastest way to make this page better for everyone.