TEAD1 — TEA Domain Transcription Factor 1

TEAD1 — TEA Domain Transcription Factor 1

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TEAD1 — TEA Domain Transcription Factor 1</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>TEAD1</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>TEA Domain Transcription Factor 1</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>TEF-1, ETF, NTEF, TEAD</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>11p15.4</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>7003</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000187091</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P28347</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>189892</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>Transcription factor; Hippo pathway effector</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Alzheimer's disease, Parkinson's disease, cancer, Svevo syndrome</td>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">YAP</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">TAZ</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">LATS1/2</td>
<td>Upstream regulation</td>
</tr>
<tr>
<td class="label">MST1/2</td>
<td>Upstream regulation</td>
</tr>
<tr>
<td class="label">VGLL proteins</td>
<td>Comp

TEAD1 — TEA Domain Transcription Factor 1

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TEAD1 — TEA Domain Transcription Factor 1</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>TEAD1</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>TEA Domain Transcription Factor 1</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>TEF-1, ETF, NTEF, TEAD</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>11p15.4</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>7003</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000187091</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P28347</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>189892</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>Transcription factor; Hippo pathway effector</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Alzheimer's disease, Parkinson's disease, cancer, Svevo syndrome</td>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">YAP</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">TAZ</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">LATS1/2</td>
<td>Upstream regulation</td>
</tr>
<tr>
<td class="label">MST1/2</td>
<td>Upstream regulation</td>
</tr>
<tr>
<td class="label">VGLL proteins</td>
<td>Competition</td>
</tr>
<tr>
<td class="label">p300</td>
<td>Coactivator</td>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">YAP</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">TAZ</td>
<td>Direct binding</td>
</tr>
<tr>
<td class="label">LATS1/2</td>
<td>Upstream regulation</td>
</tr>
<tr>
<td class="label">MST1/2</td>
<td>Upstream regulation</td>
</tr>
<tr>
<td class="label">VGLL proteins</td>
<td>Competition</td>
</tr>
<tr>
<td class="label">p300</td>
<td>Coactivator</td>
</tr>
<tr>
<td class="label">Species</td>
<td>Identity</td>
</tr>
<tr>
<td class="label">Human</td>
<td>Reference</td>
</tr>
<tr>
<td class="label">Mouse</td>
<td>97%</td>
</tr>
<tr>
<td class="label">Zebrafish</td>
<td>75%</td>
</tr>
<tr>
<td class="label">Drosophila</td>
<td>60%</td>
</tr>
<tr>
<td class="label">Agent</td>
<td>Target</td>
</tr>
<tr>
<td class="label">K-975</td>
<td>TEAD1 palmitoylation</td>
</tr>
<tr>
<td class="label">Verteporfin</td>
<td>YAP-TEAD</td>
</tr>
<tr>
<td class="label">MDM2 inhibitors</td>
<td>YAP degradation</td>
</tr>
</table>

TEAD1 (TEA Domain Transcription Factor 1), also known as transcription factor TEAD-1 or NTEF-1, is a member of the TEA domain (TEA/ATTS) transcription factor family. TEAD1 is a key effector of the Hippo signaling pathway and plays critical roles in development, tissue homeostasis, and cell fate determination. In the nervous system, TEAD1 regulates neurogenesis, neuronal survival, synaptic function, and is implicated in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease[@kakumoto2016].

Gene and Protein Structure

Gene Location

Gene Structure

The TEAD1 gene spans approximately 50 kb and consists of 16 exons encoding a 426-amino acid protein. The gene undergoes alternative splicing to generate multiple isoforms with tissue-specific expression patterns:

• TEAD1-1 — Full-length isoform (426 aa), ubiquitous expression
• TEAD1-2 — Alternative splicing isoform with different C-terminus
• TEAD1-3 — Brain-enriched isoform
• TEAD1-4 — Muscle-specific isoform

Protein Structure

TEAD1 contains distinct functional domains:

TEA Domain (1-60)

• DNA-binding domain
• Recognizes MCAT consensus sequences (5'-CTTYWAY-3')
• Also called ATTS domain
• Mediates nuclear localization and protein-protein interactions

Transcriptional Activation Domain (60-200)

• Mediates interaction with co-activators
• Contains YAP/TAZ binding site (200-400)
• Proline-rich region

YAP/TAZ Binding Domain (200-350)

• Critical for Hippo pathway signaling
• Forms complex with YAP/TAZ
• Regulated by Hippo pathway kinases

C-terminal Domain (350-426)

• Dimerization interface
• Protein-protein interactions
• Regulatory modifications

Post-Translational Modifications

TEAD1 activity is regulated by several modifications:

• Phosphorylation: Tyrosine and serine phosphorylation affects DNA binding and interactions
• Acetylation: Lysine acetylation modulates transcriptional activity
• Sumoylation: SUMO modification influences nuclear-cytoplasmic trafficking
• Ubiquitination: Regulates protein stability and degradation

Function

Hippo Pathway Signaling

TEAD1 is the central effector of the Hippo pathway[@pan2019]:

• YAP/TAZ partnership — Forms transcriptional complexes with YAP/TAZ
• DNA binding — TEAD1 binds DNA, YAP/TAZ provide transcriptional activation
• Target gene regulation — Controls genes for proliferation, survival, differentiation
• Pathway crosstalk — Interacts with Wnt, Notch, and TGF-β pathways

Cell Proliferation Control

TEAD1 regulates cell cycle genes[@arrington2017]:

• Cyclin expression — Controls cyclin D1, cyclin E
• Cell cycle arrest — Mediates contact inhibition
• Proliferation signals — Responds to growth factor signaling
• Tissue size control — Limits organ size through Hippo activation

Cell Survival

TEAD1 influences apoptosis and survival[@wang2018]:

• Anti-apoptotic genes — Activates survivin, Bcl-2 family
• Pro-apoptotic regulation — Can repress pro-death genes
• Stress responses — Handles oxidative stress, DNA damage
• Autophagy regulation — Links to autophagy pathways

Tissue-Specific Functions

TEAD1 has specialized roles in different tissues:

• Heart development — Essential for cardiogenesis
• Muscle differentiation — Myogenesis regulator
• Neural development — Neuronal specification and migration

Brain Expression and Function

Neuronal Expression

TEAD1 is widely expressed in the brain with specific patterns:

• Cerebral cortex: High expression in pyramidal neurons across all layers
• Hippocampus: Particularly enriched in CA1 and CA3 pyramidal cells
• Cerebellum: Purkinje cells show strong TEAD1 expression
• Subventricular zone: Neural stem cells express TEAD1
• Olfactory bulb: Mitral and tufted cells

Glial Expression

TEAD1 is also expressed in glial cells[@miao2022]:

• Astrocytes: TEAD1 regulates astrocyte proliferation and reactivity
• Oligodendrocytes: Controls oligodendrocyte differentiation and myelination
• Microglia: Modulates microglial activation and neuroinflammation

Transcriptional Targets

TEAD1 regulates numerous target genes in the nervous system:

• Cell cycle regulators: cyclin D1, cyclin E, p21, p27
• Survival proteins: survivin, Bcl-2, MCL-1
• Cytoskeletal proteins: actin, tubulin, MAPs
• Synaptic proteins: synapsin, PSD-95, NMDA receptors
• Metabolic enzymes: glycolysis and mitochondrial genes

Regulation

Upstream Signaling

TEAD1 activity is regulated by multiple signaling pathways:

Co-factors

TEAD1 requires co-factors for transcriptional activity:

• YAP/TAZ: Primary co-activators, form complexes with TEAD1
• VGLL proteins: Vestigial-like proteins can compete with YAP/TAZ
• p300/CBP: Histone acetyltransferases for transcriptional activation
• SMADs: TGF-β pathway effectors can cooperate with TEAD1

Cellular Localization

TEAD1 subcellular distribution is tightly regulated:

• Nuclear localization: Active transcription factor in nucleus
• Cytoplasmic sequestration: Can be retained in cytoplasm via YAP/TAZ interactions
• Activity-dependent shuttling: Neuronal activity influences nuclear-cytoplasmic distribution

Feedback Mechanisms

TEAD1 participates in multiple feedback loops:

• Autoregulation of its own expression
• Regulation of Hippo pathway components
• Cross-talk with other transcription factor pathways

Role in Neurodegeneration

Alzheimer's Disease

TEAD1 is implicated in AD through multiple mechanisms[@chen2021]:

• Tau pathology: TEAD1-mediated transcription is disrupted by tau-induced alterations
• YAP dysregulation: Aβ exposure modulates Hippo pathway activity
• Synaptic dysfunction: TEAD1 regulates synaptic plasticity genes
• Neuronal survival: Pathway dysregulation leads to increased apoptosis

Parkinson's Disease

Hippo pathway dysregulation affects dopaminergic neurons[@chen2021]:

• YAP/TAZ signaling altered in substantia nigra
• TEAD1 expression reduced in PD brain tissue
• Contributes to dopaminergic neuron vulnerability

Molecular Mechanisms

TEAD1 contributes to neurodegeneration through several mechanisms:

Animal Models

Several animal models have elucidated TEAD1 function:

• TEAD1 knockout mice: Embryonic lethal, cardiac defects
• Conditional KO models: Brain-specific deletion reveals neuronal functions
• YAP/TAZ double KO: Shows overlapping and unique functions with TEAD1
• Transgenic models: Expressing mutant TEAD1 recapitulates disease features

Therapeutic Implications

Targeting TEAD1 offers therapeutic potential[@totter2019]:

• YAP-TEAD1 interaction inhibitors — Several compounds in development
• Gene therapy approaches — Viral vector delivery
• Small molecule modulators — Pathway-specific compounds

Molecular Mechanisms

YAP/TAZ Partnership

TEAD1 functions primarily through its partnership with YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif)[@pan2019]. This partnership is central to Hippo pathway signaling:

The YAP-TEAD1 complex is regulated by Hippo pathway kinases LATS1/2, which phosphorylate YAP and TAZ, leading to their cytoplasmic retention and degradation.

DNA Binding and Target Gene Specificity

TEAD1 recognizes specific DNA sequences[@kakumoto2016]:

• MCAT elements: TEAD1 binds the consensus 5'-CTTYWAY-3'
• Multiple binding sites: Different promoters contain varying numbers of TEAD binding sites
• Cofactor influence: Partner proteins modulate DNA binding affinity and specificity
• Tissue-specific targets: Different tissues show distinct TEAD1 target gene sets

Transcriptional Regulation

TEAD1 controls numerous downstream targets:

• Proliferation genes: Cyclins, CDKs, growth factors
• Survival genes: Bcl-2, survivin, IAPs
• Differentiation factors: Developmental transcription factors
• Metabolic enzymes: Glycolysis and mitochondrial genes
• Extracellular matrix: Collagen, fibronectin components

Brain Expression and Function

Cellular Distribution

TEAD1 exhibits broad expression in the brain[@huang2020]:

• Neurons: High expression in cortical and hippocampal neurons
• Astrocytes: Moderate expression in glial cells
• Oligodendrocytes: Lower expression in myelin-producing cells
• Neural stem cells: Active expression in proliferative zones

Neurogenesis Regulation

TEAD1 plays essential roles in neural development[@arrington2017]:

• Neural stem cell maintenance: Supports proliferation of progenitor cells
• Neuronal differentiation: Controls expression of differentiation markers
• Migration regulation: Modulates neuronal positioning in developing brain
• Cortical layering: Contributes to proper cortical architecture

Synaptic Function

TEAD1 is involved in synaptic plasticity[@kim2018]:

• Synaptic protein regulation: Controls expression of synaptic components
• LTP induction: Required for long-term potentiation in hippocampus
• Memory formation: TEAD1 activity correlates with cognitive function
• Synapse stability: Maintains synaptic structure and function

Pathophysiology in Disease

Amyloid-beta Effects

In Alzheimer's disease, Aβ affects TEAD1 signaling[@wang2018]:

• Aβ exposure reduces TEAD1 nuclear localization
• YAP/TAZ partitioning is altered in AD neurons
• TEAD1 target gene expression is dysregulated
• Contributes to neuronal vulnerability and death

Tau Pathology Interaction

TEAD1 intersects with tau pathology[@liu2020]:

• Tau accumulation affects YAP/TAZ localization
• TEAD1-mediated transcription is perturbed
• Synaptic TEAD1 targets are downregulated
• Provides link between protein aggregation and transcriptional dysregulation

Neuroinflammation

TEAD1 regulates inflammatory responses[@miao2022]:

• Controls cytokine expression in glial cells
• Modulates microglial activation states
• Links inflammation to cell survival pathways
• Therapeutic targeting may provide anti-inflammatory benefits

Axonal Growth and Regeneration

TEAD1 supports neuronal regeneration[@anderson2020]:

• Promotes axonal extension in developing neurons
• YAP/TEAD1 axis contributes to repair mechanisms
• Activity decreases with aging
• Enhancement strategies may improve regeneration after injury

Therapeutic Development

Small Molecule Inhibitors

Several approaches are being developed:

• YAP-TEAD interaction disruptors: Block protein-protein binding
• TEAD1 DNA binding inhibitors: Prevent target gene activation
• Hippo pathway activators: Upstream kinase agonists

Gene Therapy Strategies

Viral vector approaches include:

• YAP/TAZ modulation: Deliver modified transcription factors
• TEAD1 knockdown: Reduce pathway activity in disease states
• Combination approaches: Target multiple pathway components

Biomarkers and Diagnostics

TEAD1 as a disease marker:

• Brain TEAD1 levels as biomarker for neurodegeneration
• YAP/TEAD1 ratio in CSF as potential indicator
• Expression changes correlating with disease stage

Interactions and Signaling Network

TEAD1 interacts with multiple signaling pathways:

See Also

• [Modulates microglial activation states](/cell-types/microglia)
• [Links inflammation to cell survival pathways](/genes/th)
• [Therapeutic targeting may provide anti-inflammatory benefits](/genes/ar)

Axonal Growth and Regeneration

TEAD1 supports neuronal regeneration[@anderson2020]:

• [Promotes axonal extension in developing neurons](/cell-types/neurons)
• [YAP/TEAD1 axis contributes to repair mechanisms](/mechanisms)
• [Activity decreases with aging](/gaps/aging)
• Enhancement strategies may improve regeneration after injury

Therapeutic Development

Small Molecule Inhibitors

Several approaches are being developed:

• YAP-TEAD interaction disruptors: Block protein-protein binding
• [TEAD1 DNA binding inhibitors*: Prevent target gene activation](/genes/ar)
• [Hippo pathway activators*: Upstream kinase agonists](/genes/th)

Gene Therapy Strategies

Viral vector approaches include:

• [YAP/TAZ modulation*: Deliver modified transcription factors](/genes/ran)
• [TEAD1 knockdown*: Reduce pathway activity in disease states](/genes/th)
• [Combination approaches*: Target mult](/genes/ar)iple pathway components

Biomarkers and Diagnostics

TEAD1 as a disease marker:

• Brain TEAD1 levels as biomarker for neurodegeneration
• YAP/TEAD1 ratio in CSF as potential indicator
• Expression changes correlating with disease stage

Interactions and Signaling Network

TEAD1 interacts with multiple signaling pathways:

Clinical Implications

Diagnostic Biomarkers

TEAD1 expression patterns show promise as diagnostic and prognostic biomarkers in neurodegeneration:

Brain tissue biomarkers: Immunohistochemical analysis of postmortem brain tissue reveals:

• Reduced TEAD1 nuclear localization in AD prefrontal cortex
• Altered YAP/TEAD1 ratio correlates with disease severity
• TEAD1 target gene expression predicts cognitive decline

• Soluble TEAD1 fragments as neuronal damage indicators
• YAP/TEAD1 ratio in extracellular vesicles
• Correlation with established biomarkers (tau, Aβ42)

• TEAD1 mRNA in peripheral blood mononuclear cells
• YAP/TEAD1 balance as systemic indicator

Therapeutic Targeting

Multiple therapeutic approaches are being developed to target TEAD1 and the Hippo pathway:

Small Molecule Inhibitors

Several classes of compounds are in development:

• Verteporfin derivatives
• Peptide mimics of TEAD interaction domains
• Allosteric inhibitors

• FL-410 (in preclinical development)
• K-975 (shown to reduce tumor growth)

• LATS1/2 activators
• MST1/2 agonists

Gene Therapy Approaches

Viral vector-mediated delivery offers another strategy:

• YAP overexpression: Deliver modified YAP variants with enhanced activity
• TEAD1 knockdown: Reduce pathological TEAD1 signaling using shRNA
• Combination therapy: Target multiple components of the pathway

Protein-Based Therapeutics

Biologic approaches include:

• YAP mimetics: Engineered YAP variants that activate TEAD1
• Decoy proteins: Soluble TEAD1 extracellular domains
• Antibody-based inhibitors: Anti-YAP or anti-TEAD1 antibodies

Evolutionary Perspective

Conservation

TEAD1 is highly conserved across evolution:

The TEA domain and YAP-binding region show the highest conservation, reflecting their essential functions.

Evolutionary Origins

The TEAD family arose from gene duplication events:

• Early metazoans: Single TEAD gene
• Vertebrates: Four family members (TEAD1-4)
• Specialized functions in different tissues

Model Systems and Research Tools

Animal Models

Multiple animal models illuminate TEAD1 function:

Zebrafish models: Transparent embryos enable real-time imaging of:

• Neural tube development
• Cell migration patterns
• YAP/TEAD1 dynamics

• TEAD1 knockout: Embryonic lethal (E10.5-14.5)
• Conditional CNS knockout: Viable with neurological phenotypes
• Transgenic overexpression: Altered brain development

• Rapid genetic screening
• Tissue-specific manipulation
• Live imaging of pathway dynamics

Cell Culture Systems

Primary neurons and cell lines provide mechanistic insights:

• Primary cortical neurons: Acute studies of YAP/TEAD1 dynamics
• iPSC-derived neurons: Patient-specific models
• Neuroblastoma lines: Stable transfection studies
• Organoid systems: Three-dimensional brain models

Future Directions

Unresolved Questions

Key knowledge gaps remain:

Emerging Research Areas

New frontiers include:

• Single-cell analysis: Understanding TEAD1 function in specific cell types
• Spatial transcriptomics: Mapping YAP/TEAD1 target genes in brain regions
• CRISPR screening: Identifying pathway modifiers and synthetic lethal interactions
• Protein structure: Developing high-resolution TEAD1-YAP structure for drug design

Clinical Trial Landscape

Current and planned trials targeting the Hippo pathway:

While no clinical trials specifically target neurodegeneration yet, the strong biological rationale supports future development.

TEAD1 in Neural Stem Cells

Stem Cell Biology

TEAD1 plays crucial roles in neural stem cell (NSC) function[@morita2022]:

Stem Cell Maintenance

• Self-renewal: TEAD1 in NSC proliferation
• Fate decisions: TEAD1 in neuronal vs. glial lineage
• Aging: TEAD1 in age-related NSC decline

Neurogenesis

• Adult neurogenesis: TEAD1 in hippocampal neurogenesis
• Developmental neurogenesis: TEAD1 in embryonic brain
• Regeneration: TEAD1 in injury-induced neurogenesis

TEAD1 in Glial Biology

Oligodendrocyte Development

TEAD1 contributes to oligodendrocyte biology[@suzuki2023]:

Myelination

• Oligodendrocyte differentiation: TEAD1 in lineage commitment
• Myelin formation: TEAD1 in myelination
• Node of Ranvier: TEAD1 in nodal complex

Demyelinating Diseases

• Multiple sclerosis: TEAD1 in MS pathophysiology[@takahashi2023]
• Therapeutic potential: Targeting Hippo pathway for remyelination

Microglial Function

TEAD1 in microglial biology[@chen2023]:

• Activation states: TEAD1 in microglial polarization
• Neuroinflammation: TEAD1-mediated inflammatory responses
• Brain homeostasis: TEAD1 in microglial surveillance

TEAD1 in Aging and Neurodegeneration

Age-Related Changes

• Expression decline: TEAD1 decreases with age
• Functional implications: Age-related TEAD1 dysfunction
• Neurodegeneration risk: Contribution to sporadic AD/PD

Therapeutic Implications

Targeting TEAD1 in aging[@yang2023]:

• Preventive strategies: Maintaining TEAD1 function
• Disease modification: Restoring Hippo pathway activity
• Combination approaches: TEAD1 with other targets

TEAD1: Knowledge Gaps and Future Directions

Unresolved Questions

Future Research Directions

• Single-cell analysis: Define TEAD1 function at single-cell resolution
• Spatial transcriptomics: Map TEAD1 target genes in brain
• CRISPR screening: Identify pathway modifiers
• Clinical translation: Develop TEAD1-targeted therapeutics

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Hippo Signaling Pathway](/mechanisms/hippo-signaling)
• [YAP/TAZ](/proteins/yap-taz)
• [Tau Protein](/proteins/tau)
• [Synaptic Function](/mechanisms/synaptic-function)

Pathway Diagram

References

Pathway Diagram

The following diagram shows the key molecular relationships involving TEAD1 — TEA Domain Transcription Factor 1 discovered through SciDEX knowledge graph analysis: