TEAD Transcription Factors: Roles in Tissue Architecture

TEAD transcription factors regulate gene expression tied to cell growth, differentiation, and organ development. Their activity is controlled through interactions with co-factors and signaling pathways, ensuring proper tissue function and structural integrity.

Given their role in cellular behavior, TEAD factors are essential for maintaining tissue architecture and coordinating proliferation. Understanding their mechanisms provides insights into developmental biology and disease progression, particularly in cancer and fibrosis.

Structural Features

TEAD transcription factors share a conserved structural framework that enables their function as DNA-binding proteins. At the core of their architecture is the TEA domain, responsible for recognizing and binding to specific DNA sequences known as MCAT elements. This domain, spanning approximately 70 amino acids, adopts a globular fold stabilized by hydrogen bonds and hydrophobic interactions. Structural studies, including X-ray crystallography and NMR spectroscopy, have shown this domain forms a three-helix bundle, facilitating high-affinity interactions with target gene promoters. The specificity of this binding is dictated by sequence recognition and conformational adaptability, allowing TEAD factors to regulate genes involved in tissue organization.

Beyond DNA binding, TEAD proteins possess a C-terminal region that serves as a docking site for transcriptional co-activators. Unlike many transcription factors with intrinsic activation domains, TEAD factors rely on co-factors such as YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) to drive gene expression. This interaction is mediated by a hydrophobic pocket within the TEAD C-terminal domain, accommodating a conserved Ω-loop motif in YAP and TAZ. Mutations disrupting this interface significantly impair TEAD-dependent transcription, highlighting its importance in cellular regulation. Additionally, post-translational modifications, including palmitoylation at a conserved cysteine residue, modulate TEAD stability and nuclear localization, fine-tuning its activity.

Signaling Pathway Intersections

TEAD transcription factors function at the crossroads of multiple signaling cascades, integrating extracellular cues to modulate gene expression. One of the most well-characterized interactions is within the Hippo signaling pathway, which regulates cell proliferation and organ size. When active, the Hippo pathway phosphorylates YAP and TAZ, leading to their sequestration in the cytoplasm and degradation. This prevents TEAD from initiating transcriptional programs associated with growth. When Hippo signaling is attenuated, YAP and TAZ translocate into the nucleus, bind TEAD, and drive gene expression linked to tissue expansion. Structural and biochemical analyses have demonstrated that the TEAD-YAP/TAZ complex is stabilized through hydrophobic and electrostatic interactions, ensuring precise transcriptional control.

Beyond Hippo signaling, TEAD factors also interface with Wnt/β-catenin signaling, which is essential for embryogenesis and tissue homeostasis. β-catenin, upon activation, accumulates in the nucleus and associates with transcriptional regulators to drive gene expression. TEAD proteins can act as co-factors in this process, forming complexes with β-catenin to enhance transcription. This synergy is particularly evident in epithelial tissues, where TEAD and β-catenin coordinate cell adhesion and polarity.

TEAD transcription factors also intersect with TGF-β signaling, which influences cellular differentiation and extracellular matrix remodeling. TEAD can modulate the transcriptional output of SMAD proteins, the primary effectors of TGF-β signaling. This interaction is particularly relevant in fibrotic diseases, where aberrant TEAD-SMAD cooperation leads to excessive extracellular matrix deposition and tissue stiffening. The mechanistic basis of this crosstalk involves direct protein-protein interactions and co-occupancy at gene promoters, allowing TEAD to integrate multiple signaling inputs.

Influence On Tissue Architecture

TEAD transcription factors shape tissue architecture by regulating gene expression programs that control cell adhesion, polarity, and extracellular matrix composition. Their role is particularly evident in epithelial tissues, where cells must maintain organization to support barrier function and organ integrity. TEAD factors regulate cell junction components, including E-cadherin and claudins, ensuring cohesive cell-cell interactions fundamental to tissue stability. Disruptions in this regulatory network have been implicated in epithelial-mesenchymal transition (EMT), where cells lose polarity and acquire migratory properties, a hallmark of fibrosis and cancer progression.

Beyond cell-cell adhesion, TEAD factors influence the extracellular matrix (ECM), a structural scaffold that provides mechanical support and biochemical cues. TEAD-mediated transcription regulates ECM proteins such as fibronectin and collagen, which contribute to tissue stiffness and resilience. In mechanically active environments, such as the lung and cardiovascular system, TEAD activity is modulated by biomechanical forces that alter nuclear localization and transcriptional output. This mechanosensitive regulation allows tissues to adapt to mechanical stress, preventing structural failure or excessive fibrosis. Studies using organoid models have demonstrated that TEAD-dependent ECM remodeling is necessary for proper tissue morphogenesis.

Relationship With Cellular Proliferation

TEAD transcription factors influence cellular proliferation by regulating genes that control the cell cycle and mitotic progression. Their ability to drive or restrain cell division depends on interactions with co-factors and signaling networks that fine-tune transcription. In highly proliferative tissues such as the intestinal epithelium and liver, TEAD factors promote the expression of cyclin genes essential for cell cycle transitions. Cyclin D1, a well-established TEAD target, facilitates the G1/S phase transition by activating cyclin-dependent kinases (CDKs), accelerating cell cycle progression. This regulatory mechanism is particularly evident during tissue regeneration, where TEAD-dependent transcription ensures a controlled proliferative response following injury.

Dysregulation of TEAD activity has been implicated in oncogenesis. In various cancers, persistent nuclear localization of YAP or TAZ leads to unchecked cell division and tumor growth. TEAD-driven transcriptional programs upregulate anti-apoptotic factors such as BIRC5 (survivin), enhancing cell survival and resistance to programmed cell death. This oncogenic potential has made TEAD a target for therapeutic interventions, with efforts underway to develop small-molecule inhibitors that disrupt its interaction with YAP/TAZ, curbing excessive proliferation in malignancies such as hepatocellular carcinoma and mesothelioma.

Methods To Investigate TEAD Factors

Investigating TEAD transcription factors requires molecular, biochemical, and genetic approaches. As TEAD proteins operate within complex signaling networks and interact with multiple co-factors, researchers employ diverse methodologies to dissect their roles in tissue architecture and cellular behavior.

Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is invaluable for mapping TEAD-binding sites across the genome. This technique identifies direct TEAD target genes and assesses how binding patterns change in response to signaling inputs. Combining ChIP-seq with RNA sequencing (RNA-seq) provides a comprehensive view of TEAD function by linking DNA occupancy to transcriptional outcomes. Additionally, CRISPR-Cas9 gene editing enables precise manipulation of TEAD genes, facilitating studies on their necessity in specific cellular contexts. Knockout and knock-in models generated using CRISPR have provided insights into how TEAD factors contribute to organ development and disease progression.

Structural and biochemical techniques also play a key role in studying TEAD activity. X-ray crystallography and cryo-electron microscopy have elucidated the three-dimensional architecture of TEAD complexes, particularly its interactions with YAP and TAZ. These structural insights have guided the development of small-molecule inhibitors targeting TEAD-cofactor binding, with potential therapeutic applications in cancer treatment. In parallel, fluorescence resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET) assays allow real-time monitoring of TEAD-protein interactions in live cells. These approaches provide dynamic insights into how TEAD activity is modulated by extracellular signals, mechanical forces, and post-translational modifications.