Epithelial Adherens Junction Signaling

Molecular structure and components of the adherens junction

Classical cadherins, a family of calcium-dependent transmembrane proteins, form the core of the adherens junction. The predominant isoform in epithelial tissues is E-cadherin, while N-cadherin and others operate in different tissues. Cadherins on adjacent cells engage in homophilic interactions, forming zipper-like adhesions across the intercellular space.

Inside the cell membrane, cadherins bind to catenins including β-catenin, p120-catenin and α-catenin. p120-catenin stabilizes cadherins at the plasma membrane. β-catenin links cadherins to α-catenin, which in turn connects the complex to filamentous actin. These protein assemblies interact dynamically with actin filaments and actomyosin, allowing adherens junctions to fluidly modulate cell shape and tissue remodeling.

Mechanism of adherens junction signaling

Adherens junction signaling integrates adhesive function with cytoskeletal regulation and intracellular signaling.

Cadherin–catenin complex formation

Cadherins cluster at cell–cell contacts and recruit catenins, forming adhesion complexes that link to the actin cytoskeleton. This cadherin–catenin scaffold serves as a hub for additional regulatory proteins that control actin organization and cell polarity.

Actin remodeling

Acting through Rho family GTPases (RhoA, Rac1, Cdc42), α-catenin and associated proteins regulate the balance between actin polymerization and contractility at the junction. This fine-tuning of cytoskeletal tension enables tissues to withstand mechanical stress while remaining flexible during morphogenesis.

Cross talk with Wnt signaling

Adherens junctions are at the intersection of adhesion and gene regulation, linking cell contact with developmental and proliferative programs. Playing a dual role, β-catenin supports adhesion at the membrane but, when released into the cytoplasm, it can translocate to the nucleus and act as a co-activator in the Wnt signaling pathway, regulating gene transcription.

Regulation of adherens junctions

Adherens junctions are dynamic complexes that are continuously remodeled in response to intracellular signaling and external stimuli. Sources of their regulation include: post-translational modification, Rho family GTPases, Mechanical regulation and External cues and developmental signals.

Post-translational modification

Tyrosine phosphorylation of junctional proteins such as β-catenin and p120-catenin weakens their association with cadherins, leading to destabilization of cadherin–catenin complexes. In contrast, dephosphorylation stabilizes these complexes, reinforcing adhesion under homeostatic conditions.

Rho family GTPases

The Rho family of small GTPases are also involved in regulation of adherens junctions. RhoA activity promotes actomyosin contractility and stress fiber formation, stabilizing adherens junctions by enhancing cadherin–actin anchoring. Rac1 and Cdc42 also support junction integrity by stimulating actin polymerization and lamellipodia or filopodia formation, allowing junctions to extend and remodel during tissue morphogenesis.

Mechanical regulation

Myosin II–generated contractility exerts pulling forces on cadherin–catenin complexes, which paradoxically strengthens adhesion by promoting cadherin clustering and reinforcing actin linkage. This ability to convert mechanical forces into biochemical signals ensures that epithelial tissues remain cohesive under stress.

External cues and developmental signals

Growth factors, cytokines, and hormones dynamically influence adherens junctions. Wnt signaling modulates adherens junctions by regulating the availability of β-catenin for adhesion versus transcriptional signaling. While hormonal signals, such as estrogen and thyroid hormone, alter cadherin and catenin expression, further influencing junctional stability.

Biological functions

Adherens junctions play essential roles in epithelial physiology, development, and disease.

Tissue morphogenesis and development

During embryogenesis, adherens junctions drive morphogenetic movements such as epithelial sheet folding, tube formation and boundary establishment. Their ability to couple adhesion with actin remodeling allows tissues to change shape while maintaining integrity.

Maintenance of epithelial integrity

In adult tissues, adherens junctions preserve epithelial polarity and barrier function. By linking neighboring cells and coordinating cytoskeletal networks, they provide resilience against mechanical stress.

Regulation of cell migration

Dynamic remodeling of adherens junctions permits controlled cell migration during processes such as wound healing. Coordinated junctional turnover allows epithelial sheets to move collectively without losing cohesion.

Mechanosensation

Adherens junctions function as mechanosensors, adjusting adhesion strength in response to changes in tissue tension.

Clinical relevance of adherens junction dysfunction

Loss or dysregulation of adherens junctions is implicated in a wide range of diseases. For example, downregulation or mutation of E-cadherin is a hallmark of epithelial–mesenchymal transition (EMT) – a process that is central to cancer invasion and metastasis. Altered adherens junction signaling is also implicated in inflammatory diseases, vascular disorders and developmental abnormalities.

References

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