TEAD3

TEAD3 is a TEA-domain transcription factor that binds MCAT/GT-IIC/SphI enhancer elements to activate gene expression programs in placental trophoblasts, cardiac myocytes, myoblasts, Schwann cells, and osteogenic progenitors. TEAD3 cooperates with the co-activators YAP and VGLL3 to drive target gene transcription, but also functions in YAP-independent contexts such as HLA-G regulation in extravillous trophoblasts and cholesterol biosynthesis gene control in glioblastoma stem cells (PMID:31138678, PMID:40096597, PMID:40457844). Its DNA-binding activity is modulated by phosphorylation downstream of α1-adrenergic signaling and by arginine methylation at R55, which controls TEA-domain homodimerization and condensate formation that can sequester RUNX2 to suppress osteogenic differentiation (PMID:11986313, PMID:41556418). TEAD3 harbors a palmitoylation pocket enabling isoform-selective covalent inhibition, and it acts redundantly with TEAD4 in trophectoderm specification during preimplantation development (PMID:34729310, PMID:39679917).

1. 1997 High

   Establishing that TEAD3 directly and cooperatively binds GT-IIC/SphI enhancer elements answered the fundamental question of which transcription factor family member engages placental enhancers, grounding TEAD3 as a sequence-specific DNA-binding protein.

   Evidence EMSA with monoclonal antibody supershift and site-directed mutagenesis of the human chorionic somatomammotropin-B enhancer

   PMID:9148898

   Open questions at the time

   • Cooperativity mechanism at the structural level not resolved
   • In vivo chromatin occupancy not tested
2. 1999 High

   Demonstrating that full-length TEAD3 transactivates GT-IIC-dependent enhancers but not unrelated (OCT) enhancers established TEAD3 as an activating transcription factor with target-element specificity, and identified a role for its 5′ UTR in controlling protein production.

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

   PMID:10379887

   Open questions at the time

   • Activation domain boundaries not mapped
   • Endogenous chromatin targets not identified
3. 2002 High

   Showing that TEAD3 is phosphorylated in vivo and that α1-adrenergic signaling enhances its DNA-binding activity in cardiac myocytes revealed the first post-translational regulatory mechanism for this factor, linking it to signal-responsive gene control in the heart.

   Evidence 32P metabolic labeling, immunoprecipitation, EMSA with phosphatase treatment, and TEF-1/DTEF-1 chimeric factor analysis in neonatal rat cardiomyocytes

   PMID:11986313

   Open questions at the time

   • Specific phosphorylation sites not mapped
   • Responsible kinase not identified
   • Downstream cardiac gene targets not determined
4. 2019 High

   Identification of VGLL3 as a Hippo-kinase-independent TEAD3 co-activator in myoblasts, alongside the YAP-TEAD3 interaction during cardiomyocyte differentiation, established that TEAD3 integrates inputs from multiple co-activator families to control distinct transcriptional programs.

   Evidence Co-IP mass spectrometry and siRNA/overexpression in myoblasts (VGLL3); Co-IP and siRNA in hiPSC-derived cardiovascular progenitors (YAP)

   PMID:31138678 PMID:31541452

   Open questions at the time

   • Whether VGLL3 and YAP compete for the same TEAD3 interface not tested
   • Direct promoter occupancy by VGLL3-TEAD3 not shown
5. 2021 High

   Discovery that a covalent inhibitor targeting the TEAD3 palmitoylation pocket achieves >100-fold isoform selectivity demonstrated that TEAD paralogs have druggably distinct lipid-binding sites, and that TEAD3 activity is required for zebrafish appendage growth.

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

   PMID:34729310

   Open questions at the time

   • Crystal structure of inhibitor-TEAD3 complex not reported
   • Selectivity mechanism at atomic level unknown
6. 2025 High

   Multiple studies converged to define TEAD3's YAP-independent functions: TEAD3 is required for HLA-G transcription in trophoblasts without YAP involvement, and TEAD3-selective inhibition in glioblastoma stem cells specifically disrupts cholesterol biosynthesis genes rather than proliferation, separating TEAD3's transcriptional outputs from canonical Hippo-YAP signaling.

   Evidence Genome-wide CRISPR knockout screen in extravillous trophoblasts; TEAD3-selective pharmacological inhibition with transcriptomics in patient-derived glioblastoma stem cells

   PMID:40096597 PMID:40457844

   Open questions at the time

   • Mechanism of YAP-independent TEAD3 activation unknown
   • Cholesterol pathway regulation not validated by genetic TEAD3 knockout
   • Cofactor(s) mediating YAP-independent activity not identified
7. 2025 Medium

   Establishing functional redundancy between TEAD3 and TEAD4 in trophectoderm specification, and positioning TEAD3 within a RhoA/YAP1/CDK2 axis controlling Schwann cell myelination, expanded TEAD3's known developmental roles and placed it within a defined signaling epistasis in the peripheral nervous system.

   Evidence RNAi and base editing with scRNA-seq in bovine preimplantation embryos; conditional RhoA knockout with CDK2 rescue in mouse Schwann cells

   PMID:39679917 PMID:41178531

   Open questions at the time

   • TEAD3-specific contribution versus TEAD4 in trophectoderm not separable by single KD
   • Direct TEAD3 knockout in Schwann cells not performed
   • TEAD3-CDK2 promoter occupancy not demonstrated
8. 2026 High

   Identification of R55 arginine methylation as a switch controlling TEAD3 homodimerization, condensate formation, and RUNX2 sequestration during osteogenesis revealed a non-canonical PTM mechanism that operates independently of Hippo signaling and governs lineage commitment via phase separation.

   Evidence Arginine methylation mapping, R55K mutagenesis, phase-separation imaging, reporter assays, and PDLSC osteogenic differentiation

   PMID:41556418

   Open questions at the time

   • Methyltransferase responsible for R55 methylation not identified
   • In vivo bone phenotype not reported
   • Whether R55 methylation status changes dynamically during differentiation not tracked

• Key open questions include the identity of kinases and methyltransferases that regulate TEAD3, the structural basis for isoform-selective drug binding, the cofactors mediating YAP-independent transcription, and whether TEAD3 condensate formation is a general regulatory mechanism across tissues.
• No kinase identified for signal-responsive phosphorylation
• No methyltransferase identified for R55
• No genome-wide chromatin occupancy map for TEAD3 in any tissue
• Structural basis of palmitoylation pocket isoform selectivity unresolved