TEAD3 Transcription Factor: A Comprehensive Analysis from Molecular Characteristics to Disease Associations

Structural Features and DNA-Binding Specificity of TEAD3

As a key member of the TEAD transcription factor family, TEAD3 exhibits unique structural characteristics and precise DNA recognition mechanisms. The protein contains a highly conserved TEA domain—a ~70-amino-acid DNA-binding module that adopts a distinctive "cloverleaf-like" folded conformation, enabling specific recognition and binding to the MCAT element (5'-CATTCC-3') in the genome. X-ray crystallography reveals subtle differences in the DNA-binding interface of TEAD3 compared to TEAD1/2, with the lysine residue at position 52 playing a decisive role in DNA recognition specificity. The C-terminal region of TEAD3 harbors a canonical YAP/TAZ-binding domain, which forms a hydrophobic pocket critical for transcriptional activity through interactions with coactivators. Cryo-EM studies demonstrate that the TEAD3-YAP complex exhibits a unique spatial conformation, with a 5–7-degree difference in binding angle compared to TEAD1/2 complexes, potentially explaining TEAD3's functional specificity in certain biological processes. Mass spectrometry analyses have identified multiple post-translational modifications of TEAD3, including S-palmitoylation, phosphorylation, and SUMOylation, which dynamically regulate its nucleocytoplasmic shuttling, protein stability, and transcriptional activity. Notably, TEAD3's palmitoylation site (Cys359) differs from that of other TEAD family members, offering a potential opportunity for developing specific targeted drugs.

Central Role in Placental Development and Pregnancy Maintenance

TEAD3 plays an indispensable role in mammalian reproductive biology, particularly in placental development and pregnancy maintenance. Gene knockout studies show that TEAD3 deficiency leads to embryonic implantation failure and early pregnancy termination in mice, closely resembling the pathological features of recurrent miscarriage in humans. At the molecular level, TEAD3 regulates the expression of genes involved in trophoblast stem cell proliferation and differentiation, participating in placental villus formation and vascular remodeling. Single-cell transcriptomic analyses reveal differential expression patterns of TEAD3 in cytotrophoblasts and syncytiotrophoblasts, where it governs distinct gene networks: in proliferative cytotrophoblasts, it primarily controls cell cycle progression, while in differentiated syncytiotrophoblasts, it regulates hormone synthesis and nutrient transport functions. Notably, TEAD3 exhibits unique allele-specific expression patterns in human placental development, potentially linked to genomic imprinting mechanisms. Clinical studies indicate aberrant TEAD3 expression in placental tissues from patients with preeclampsia and fetal growth restriction, with its downstream target genes involved in key pathways of angiogenesis and immune regulation. These findings deepen our understanding of placental biology and provide new molecular targets for diagnosing and treating pregnancy-related disorders.

Complex Regulatory Network in Cancer Development and Progression

TEAD3 displays a unique duality in tumor biology, with its role highly dependent on cancer type and molecular context. Clinical sample analyses reveal frequent TEAD3 overexpression in ovarian, endometrial, and breast cancers, significantly correlating with poor prognosis. Mechanistically, TEAD3 integrates Hippo pathway signaling and hormone receptor signaling to activate pro-tumorigenic gene expression programs. For example, in estrogen receptor-positive breast cancer, TEAD3 directly forms transcriptional complexes with ERα to co-regulate proliferation-related genes like cyclin D1 and c-Myc. Protein interactome studies show that TEAD3 recruits unique cofactor combinations in tumor cells, including chromatin remodelers and histone modifiers, endowing it with specialized functions in epigenetic regulation. Notably, TEAD3 exhibits metabolic reprogramming capabilities in certain cancers by upregulating glycolysis-related genes such as GLUT1 and HK2, promoting the Warburg effect. Paradoxically, however, TEAD3 demonstrates tumor-suppressive properties in colorectal cancer and specific lung cancer subtypes. Research indicates that TEAD3 can competitively bind promoter regions to inhibit pro-oncogenic signaling pathways like β-catenin/TCF and NF-κB, contrasting sharply with its role in hormone-dependent tumors. This tissue-specific functional divergence reflects the profound influence of the tumor microenvironment on transcription factor activity and poses challenges for developing precision therapies.

Potential Roles in Nervous System Development and Function

Although research on TEAD3 in the nervous system is relatively limited, recent evidence suggests its potential importance in neural development and function. Developmental expression profiling shows enriched TEAD3 expression in specific embryonic brain regions like the thalamus and hypothalamus, implicating its role in patterning these areas. In the adult brain, TEAD3 is primarily localized to limbic structures such as the hippocampus and amygdala, which are closely associated with emotional regulation and memory formation. Preliminary electrophysiological studies indicate a positive correlation between TEAD3 expression levels and synaptic plasticity-related genes, suggesting its involvement in fine-tuning neural circuitry. In disease contexts, genome-wide association studies (GWAS) have identified weak but significant links between the TEAD3 locus and psychiatric disorders like schizophrenia and depression. Molecular analyses reveal that these risk-associated SNPs are often located in TEAD3 regulatory regions, potentially affecting its expression or transcriptional activity. Notably, aberrant TEAD3 expression has been observed in the hippocampal tissues of Alzheimer's disease patients, with changes correlating with disease stages, implying TEAD3's involvement in neurodegenerative processes. Animal model studies also show that conditional TEAD3 overexpression can mitigate β-amyloid-induced synaptic damage, possibly through regulating neurotrophic factor expression. While preliminary, these findings open new research avenues for understanding TEAD3's functions in the nervous system.

Therapeutic Strategies Targeting TEAD3 and Development Challenges

Developing TEAD3-targeted interventions faces unique challenges due to its physiological importance in reproductive and nervous systems and high homology with other TEAD family members. Current potential targeting approaches fall into three categories: specific inhibition of TEAD3 transcriptional activity, disruption of TEAD3-cofactor interactions, and modulation of TEAD3 expression levels. Structure-based drug design has yielded several small-molecule compounds, such as modified flufenamic acid derivatives, which selectively bind TEAD3's palmitoylation pocket, inducing conformational changes that suppress its transcriptional activity. These compounds show antitumor effects in endometrial and ovarian cancer models. Another strategy involves peptide inhibitors designed to block TEAD3 interactions with specific cofactors like YAP or ERα, theoretically preserving TEAD3's other functions. In gene therapy, antisense oligonucleotides (ASOs) and siRNA technologies are being explored to selectively regulate TEAD3 expression, significantly inhibiting the growth of hormone-dependent tumors in preclinical studies. However, these methods encounter major hurdles: TEAD3's critical role in placental development may cause reproductive toxicity; structural similarities with other TEAD proteins make designing highly selective inhibitors exceptionally difficult; and reliable biomarkers for patient stratification are lacking. To address these issues, next-generation research is exploring allosteric inhibitors, conditionally activated degraders, and tissue-specific delivery systems, combined with multi-omics analysis for precise intervention.

Future Research Directions and Translational Prospects

The TEAD3 research field is advancing toward greater depth and systematic exploration, with several breakthroughs anticipated. Single-cell multi-omics technologies will map cell-specific regulatory networks of TEAD3 across tissues and disease states, providing a molecular basis for understanding its functional diversity. Advanced gene-editing tools like base editing and epigenetic regulators will enable precise manipulation of TEAD3 activity, validating the importance of specific functional domains in disease models. In drug development, AI-powered virtual screening and structure-guided rational design will accelerate the discovery of novel TEAD3 modulators, while bispecific molecules and antibody-drug conjugate technologies may enhance targeting specificity. Clinically, intervention strategies for TEAD3-overexpressing gynecological cancers (e.g., ovarian and endometrial cancers) are transitioning from bench to bedside, with preliminary data suggesting TEAD3 expression levels as predictive biomarkers. Another potential avenue involves exploring TEAD3 modulation in reproductive medicine, as animal studies show that fine-tuning TEAD3 activity can ameliorate placental dysfunction. As these studies progress, TEAD3-targeted therapies are expected to advance from basic research to clinical translation within 5–10 years, offering new strategies for treating cancers and pregnancy-related disorders. Concurrently, deeper investigations into TEAD3's roles in the nervous system may unveil novel therapeutic pathways for neuropsychiatric diseases. Together, these developments will elevate TEAD3 from a relatively "niche" transcription factor to a molecular target of significant clinical value.

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