TEAD3

TEAD3 is a TEA-domain transcription factor that binds GT-IIC/MCAT and SphI/SphII cis-elements to directly activate developmental and tissue-specific target genes, including the human chorionic somatomammotropin-B (hCS-B) enhancer, where it engages tandemly repeated enhansons cooperatively and is exquisitely sensitive to single-base mutations in the binding site (PMID:9148898, PMID:10379887). Its DNA-binding and transactivation output is controlled by post-translational modification: phosphorylation enhances MCAT binding under alpha1-adrenergic stimulation in cardiac myocytes (in contrast to the opposite effect seen on TEF-1) (PMID:11986313), and methylation of arginine 55 within the TEA domain restrains formation of TEAD3 homodimer condensates that otherwise spatially sequester RUNX2 to repress osteogenic differentiation (PMID:41556418). TEAD3 partners with the co-activators YAP and VGLL3, with VGLL3 engaging TEAD3 independently of the Hippo kinase cascade (PMID:31138678, PMID:31541452). Through these interactions and DNA-binding activities TEAD3 governs differentiation across multiple lineages: cardiac lineage commitment of iPSC-derived cardiovascular progenitors via YAP (PMID:31541452), trophectoderm and extravillous trophoblast programs—including YAP-independent HLA-G transcription and KRT8/KRT18/EZR-dependent blastocyst formation (PMID:40096597, PMID:39679917)—and osteoclastogenesis, where TEAD3 activates the master regulator NFATC1 and is blocked from doing so by the lncRNA MALAT1 (PMID:36993303). A covalent inhibitor targeting the TEAD3 palmitoylation pocket selectively suppresses its transcriptional activity and constrains proportional appendage growth in zebrafish (PMID:34729310).

1. 1997 Medium

   Established TEAD3 (hTEF-5) as a sequence-specific DNA-binding factor by showing it recognizes functional enhansons of the hCS-B enhancer, with allele-discriminating sensitivity to single-base changes.

   Evidence EMSA, enhancer-element mutagenesis, and antibody disruption of TEA-domain binding

   PMID:9148898

   Open questions at the time

   • Did not define co-activator requirements or in vivo target gene set
   • Mechanism of cooperative binding to tandem elements not resolved structurally
2. 1999 Medium

   Connected TEAD3 DNA binding to functional output by demonstrating GT-IIC/SphI element binding and transactivation of hCS and SV40 enhancers, and showed untranslated regions modulate its expression.

   Evidence In vitro transcription/translation, EMSA, and transient reporter assays in BeWo cells

   PMID:10379887

   Open questions at the time

   • Did not identify co-activators driving transactivation
   • Element specificity (GT-IIC vs OCT) characterized in vitro only
3. 2002 Medium

   Identified phosphorylation as a positive regulator of TEAD3 DNA binding, linking alpha1-adrenergic signaling to MCAT-driven muscle gene activation and distinguishing TEAD3 regulation from TEF-1.

   Evidence Orthophosphate labeling, IP of tagged DTEF-1, EMSA with phosphatase treatment, and reporter assays in rat cardiac myocytes

   PMID:11986313

   Open questions at the time

   • Phosphosites and responsible kinase not mapped
   • Used mouse ortholog DTEF-1; human residue conservation not addressed
4. 2019 Medium

   Defined the co-activator landscape of TEAD3, showing VGLL3 binds TEAD3 independently of the Hippo kinase cascade while YAP couples TEAD3 to cardiac lineage commitment.

   Evidence Interaction proteomics in myoblasts/myotubes; Co-IP and RNAi phenocopy of verteporfin in iPSC cardiac differentiation

   PMID:31138678 PMID:31541452

   Open questions at the time

   • Direct target genes downstream of YAP-TEAD3 in cardiac progenitors not defined
   • VGLL3 vs YAP target-gene partitioning unresolved
5. 2021 Medium

   Demonstrated the palmitoylation pocket is a tractable regulatory site, with a TEAD3-selective covalent inhibitor revealing a role in controlling proportional appendage growth.

   Evidence Activity-based protein profiling, GAL4-TEAD reporter assays, IC50 measurements, and zebrafish fin growth assay

   PMID:34729310

   Open questions at the time

   • Endogenous lipid modification stoichiometry and physiological regulator not defined
   • Mammalian growth-control targets not identified
6. 2023 Medium

   Showed TEAD3 activity is gated by a non-coding RNA, with MALAT1 binding TEAD3 to block NFATC1 activation and thereby restrain osteoclast differentiation.

   Evidence RNA-protein binding assay and genetic knockout/rescue in mice with target-gene analysis (preprint)

   PMID:36993303

   Open questions at the time

   • Preprint, not yet peer-reviewed
   • Binding interface between MALAT1 and TEAD3 not mapped
7. 2025 Medium

   Extended TEAD3's developmental roles to trophoblast biology, establishing requirement for YAP-independent HLA-G transcription in EVT and redundant control of trophectoderm fate.

   Evidence Genome-wide CRISPR-Cas9 screen in EVT cells; siRNA/base-editing dual knockdown with scRNA-seq in bovine embryos

   PMID:39679917 PMID:40096597

   Open questions at the time

   • Co-activator(s) supporting YAP-independent activation not identified
   • Direct vs indirect control of KRT8/KRT18/EZR not distinguished
8. 2026 Medium

   Revealed arginine methylation as a switch controlling TEAD3 biophysical state, where R55 methylation limits homodimer condensate formation that otherwise sequesters RUNX2 to repress osteogenesis.

   Evidence Arginine methylation mapping, R55K mutagenesis, condensate and RUNX2 reporter assays, TEA-domain peptide sensitivity

   PMID:41556418

   Open questions at the time

   • Methyltransferase responsible for R55 not identified
   • Relationship between condensate state and canonical DNA binding not fully resolved

• The full set of direct TEAD3 target genes and the rules partitioning its co-activators (YAP vs VGLL3) and modifications (phosphorylation, methylation, palmitoylation) across distinct differentiation programs remain undefined.
• No genome-wide direct binding map across tissues
• Enzymes controlling each PTM mostly unidentified
• Isoform-specific functions vs TEAD1/TEAD4 incompletely separated