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Cell junction

Cell junctions are specialized, protein-mediated structures that connect adjacent cells within tissues, facilitating mechanical adhesion, intercellular communication, and the formation of selective barriers to regulate the passage of molecules and ions between cells or between cells and the extracellular environment.^[1] These junctions are particularly abundant in epithelial and endothelial tissues, where they maintain tissue integrity, polarity, and homeostasis by linking the plasma membranes of neighboring cells in structurally and biochemically differentiated regions.^[2] Cell junctions are broadly classified into three main functional categories: anchoring junctions, occluding (tight) junctions, and communicating (gap) junctions. Anchoring junctions, including adherens junctions and desmosomes, provide mechanical strength by linking the actin cytoskeleton or intermediate filaments of adjacent cells, enabling tissues to withstand mechanical stress.^[1] Occluding junctions, such as tight junctions, form a seal between cells to prevent paracellular leakage and establish apical-basal polarity, while also regulating selective permeability.^[1] Communicating junctions, such as gap junctions in animals and plasmodesmata in plants, create channels that allow the direct exchange of small molecules, ions, and electrical signals between cytoplasms, supporting coordinated cellular activities like synchronized contractions in cardiac muscle.^[2] Beyond their structural roles, cell junctions are integral to physiological processes such as tissue morphogenesis, barrier function in organs like the gut and blood-brain barrier, and signal transduction pathways that influence cell proliferation and differentiation.^[1] Dysregulation of these junctions is implicated in numerous pathologies, including cancer metastasis—where loss of adhesion promotes invasion—inflammatory diseases due to barrier breakdown, and inherited disorders affecting tissue stability.^[1] Research highlights their dynamic regulation by cytoskeletal elements, signaling molecules, and environmental cues, underscoring their adaptability in health and disease.^[3]

Overview

Definition and Classification

Cell junctions are multiprotein assemblies embedded in the plasma membrane that mediate adhesion between adjacent cells or between a cell and the extracellular matrix (ECM), thereby enabling tissue integrity, intercellular communication, and selective barrier functions.^[1] These structures integrate transmembrane adhesion molecules with intracellular scaffolds and cytoskeletal elements to transduce mechanical and biochemical signals across cell interfaces.^[4] The concept of cell junctions emerged from electron microscopy studies in the 1960s, where Marilyn G. Farquhar and George E. Palade first delineated junctional complexes in epithelial tissues, identifying distinct zones of membrane apposition that varied by tissue type.^[5] Their work in amphibian skin and other epithelia revealed a tripartite organization, laying the groundwork for understanding these structures as specialized domains rather than uniform contacts. Functionally, cell junctions are categorized into three main types: anchoring junctions, which mechanically link cells to one another or to the ECM through cytoskeletal attachments (the term "anchoring" derives from this tethering role); communicating junctions, which permit the passage of ions and small molecules for direct cytoplasmic continuity; and occluding junctions, which seal intercellular spaces to prevent unregulated leakage.^[2] Structurally, they further divide into cell-cell junctions, such as those forming belts or spots between neighbors, and cell-ECM junctions, which connect via integrin-based focal adhesions or hemidesmosomes to the basement membrane.^[4] This dual classification underscores their versatility in multicellular organization. For instance, adherens junctions represent anchoring types, while gap junctions exemplify communicating ones.^[1] Across eukaryotes, these mechanisms show evolutionary conservation; in plants, plasmodesmata function analogously to animal communicating junctions by forming cytoplasmic channels through cell walls, facilitating symplastic transport and signaling.^[6]

Biological Importance

Cell junctions are essential for maintaining the structural integrity of tissues, particularly in epithelia where they anchor cells together to resist mechanical stresses such as shear forces and tissue remodeling during organ development. By linking the cytoskeletons of adjacent cells, these junctions prevent dissociation and ensure the cohesion of epithelial sheets, which is critical for forming functional organs like the skin, intestines, and lungs. For instance, anchoring junctions provide mechanical stability, while occluding junctions establish selective barriers to maintain compartmentalization.^[1] From an evolutionary standpoint, cell junctions arose approximately 1.7 billion years ago alongside the transition to multicellularity in eukaryotes, enabling the stable adhesion required for collective cellular behaviors. These structures are highly conserved across metazoans, from simple sponges—which possess primitive adherens-like junctions—to complex human tissues, underscoring their fundamental role in animal development. In plants, analogous communicating junctions like plasmodesmata evolved as specialized adaptations for intercellular connectivity.^[7]^[8]^[9] Cell junctions contribute to physiological homeostasis by facilitating coordinated cellular responses in processes such as embryonic development, where they guide tissue morphogenesis; wound healing, through dynamic remodeling to restore barriers; and immune surveillance, by modulating epithelial permeability to immune cells. In development, junctions synchronize cell division and migration, while in wound repair, gap and tight junctions propagate signals for proliferation and inflammation resolution. Their disruption impairs these coordinated behaviors, leading to pathological states.^[10]^[11] Their loss or dysfunction is implicated in the progression of epithelial cancers, which account for about 90% of human malignancies and often involve reduced junctional integrity to promote invasion and metastasis.^[12]^[13] Furthermore, cell junctions interplay with epithelial polarity by delineating apical-basal domains, where tight junctions act as a boundary to segregate membrane proteins and lipids, ensuring vectorial transport and tissue function. This polarity establishment is vital for specialized roles like absorption in the gut or secretion in glands.^[14]

Anchoring Junctions

Adherens Junctions

Adherens junctions form dynamic cell-cell adhesions that anchor the actin cytoskeleton of adjacent cells, enabling mechanical coupling and tissue integrity. These junctions consist of transmembrane classical cadherins, such as E-cadherin, which mediate homophilic interactions across the intercellular space through their extracellular domains. Intracellularly, the cadherin cytoplasmic tails bind β-catenin, which in turn associates with α-catenin to link the complex to actin filaments, forming a plaque-like structure that transmits forces between cells.^[15]^[16]^[17] Adherens junctions manifest in two primary subtypes based on their morphology and distribution: zonula adherens and puncta adherens. Zonula adherens appear as continuous, belt-like bands encircling the apical region of epithelial cells, providing circumferential adhesion just below tight junctions. In contrast, puncta adherens form discrete, spot-like clusters, often observed in non-epithelial tissues such as neurons and cardiac or skeletal muscle, where they facilitate localized actin anchorage.^[18]^[19] The assembly of adherens junctions begins with the initiation of cell-cell contact, primarily driven by nectins, calcium-independent adhesion molecules that recruit cadherins to nascent junctions. Cadherin clustering then occurs in a calcium-dependent manner, where extracellular calcium ions stabilize cis and trans interactions between cadherin molecules, promoting lateral dimerization and strand-swapping in their EC1 domains. This clustering is subsequently reinforced intracellularly by afadin, which binds nectins and interacts with α-catenin, and by vinculin, which is recruited to α-catenin under tension to strengthen actin linkages and enhance junction stability.^[20]^[16]^[21] In morphogenesis, adherens junctions play a critical role in orchestrating cell shape changes through actomyosin contractility, where myosin II-driven contraction at junctional actin belts generates apical constriction. This mechanism is essential for processes like gastrulation, where endodermal precursors invaginate in organisms such as Caenorhabditis elegans and vertebrates, and neural tube closure, where convergent extension and bending rely on coordinated junction remodeling to form the embryonic neural axis.^[22]^[23]^[24] Adherens junctions are prominently distributed in tissues requiring robust intercellular cohesion and contractility, including epithelial sheets for barrier formation, endothelial linings for vascular stability, and cardiac muscle at intercalated discs to synchronize contractions.^[25]^[1]^[26]

Desmosomes

Desmosomes are specialized anchoring junctions that provide mechanical stability to tissues by linking adjacent cells through intermediate filaments, forming a robust network capable of withstanding significant tensile forces. These junctions consist of a plaque-like cytoplasmic density, approximately 0.2–0.5 μm in diameter, where transmembrane desmosomal cadherins—desmogleins (Dsg1–4) and desmocollins (Dsc1–3)—mediate calcium-dependent cell-cell adhesion via their extracellular domains. Intracellularly, these cadherins associate with armadillo family proteins such as plakoglobin and plakophilins (Pkp1–3), which in turn recruit desmoplakin, a plakin family member that anchors keratin intermediate filaments to the plaque, thereby integrating the cytoskeletal framework across cells.^[27]^[28] The assembly of desmosomes occurs through a sequential recruitment process initiated by the vesicular transport of desmosomal cadherins to the plasma membrane, where desmocollin 2 typically nucleates the junction, followed by desmoglein 2. Armadillo proteins like plakoglobin then cluster these cadherins, facilitating the incorporation of plakophilins and desmoplakin, which accumulates at contacts within minutes and stabilizes the structure in an actin-dependent manner. This dynamic process can be disrupted by autoantibodies targeting desmoglein 3, as seen in pemphigus vulgaris, highlighting the junction's sensitivity to specific molecular perturbations.^[29]^[28] In stratified epithelia, desmosomes exhibit adaptations such as a hyper-adhesive state that develops over days, rendering adhesions partially calcium-independent and enhancing resistance to shear forces. Unlike adherens junctions, which link to dynamic actin filaments, desmosomes connect to resilient keratin intermediate filaments.^[27]^[28]^[30] Desmosomes play critical roles in tissues subjected to high mechanical demands, such as the epidermis where they maintain skin barrier function, the cardiac intercalated discs where mutations in components like desmoplakin contribute to arrhythmogenic cardiomyopathy, and mucosal linings for overall tissue cohesion. These junctions are evolutionarily ancient, emerging early in metazoan history to confer enhanced intercellular adhesion in multicellular organisms.^[27]^[30]

Hemidesmosomes

Hemidesmosomes are stable anchoring junctions that resemble half-desmosomes, featuring electron-dense plaques on the cytoplasmic side of the basal plasma membrane in epithelial cells. These structures connect the basal surface of keratinocytes to the underlying basement membrane through the transmembrane α6β4 integrin, which binds extracellularly to laminin-332 in the extracellular matrix (ECM).^[31] Intracellularly, the β4 subunit of the integrin associates with plaque proteins such as plectin and BP230 (also known as bullous pemphigoid antigen 1, BPAG1-e), which in turn anchor to keratin intermediate filaments, providing mechanical stability.^[31] This organization ensures robust attachment, with hemidesmosomes appearing as small, submicron electron-dense domains distributed across the ventral surface of basal keratinocytes.^[31] Assembly of hemidesmosomes begins with the activation and clustering of α6β4 integrins triggered by binding to laminin-332, a heterotrimeric ECM protein secreted by keratinocytes.^[32] This interaction promotes recruitment of intracellular plaque components, including plectin and BP230, to form the stabilizing cytoplasmic plaque, which links to keratin filaments.^[32] Unlike the more dynamic focal adhesions, hemidesmosomes exhibit a stable, plaque-like organization that resists mechanical stress and turnover, supporting long-term adhesion rather than migratory processes.^[33] Hemidesmosomes are primarily concentrated at the basal lamina in stratified epithelia, such as the epidermis, facilitating uniform attachment. They provide essential long-term anchorage for tissue layering by mechanically coupling the cytoskeleton to the ECM, thereby maintaining epidermal-dermal cohesion and preventing separation under shear forces.^[32] Mutations in hemidesmosomal components disrupt this adhesion, leading to epidermolysis bullosa (EB), a group of inherited blistering skin disorders. For instance, defects in BP180 (collagen XVII), a transmembrane collagen that stabilizes the integrin-plaque linkage, cause junctional EB with skin fragility and blistering due to impaired dermo-epidermal attachment.^[34] Similar to desmosomes, hemidesmosomes link to intermediate filaments intracellularly but specifically target the ECM for basal anchorage.^[31]

Communicating Junctions

Gap Junctions

Gap junctions are specialized intercellular channels that facilitate direct cytoplasmic continuity between adjacent animal cells, enabling the exchange of ions, metabolites, and signaling molecules to support metabolic and electrical coupling. These structures consist of paired hemichannels, known as connexons, each formed by the oligomerization of six connexin proteins into a hexameric assembly that spans the plasma membrane. In tissues such as the heart, connexin 43 (Cx43) is a predominant isoform, forming these connexons that dock end-to-end across a narrow extracellular gap of approximately 2-4 nm, creating a continuous aqueous pore.^[35]^[36] The pore diameter of gap junctions typically ranges from 8 to 16 Å, rendering them selectively permeable to small hydrophilic molecules under 1 kDa, including ions like potassium and calcium, as well as second messengers such as cyclic AMP (cAMP) and inositol trisphosphate. This size selectivity varies with the connexin isoform, ensuring efficient passage of regulatory signals while excluding larger macromolecules. The resulting channel permits a flux of approximately 10^3 dye molecules per second under typical concentration gradients, as measured for tracers like Lucifer Yellow in Cx43-based junctions.^[37]^[38] Assembly of gap junctions begins with the synthesis and trafficking of connexin monomers through the endoplasmic reticulum and Golgi apparatus, where they oligomerize into hemichannels within post-Golgi vesicles before insertion into the plasma membrane. Docking of opposing hemichannels from adjacent cells occurs via specific extracellular loops, stabilizing the structure and opening the channel. Gating mechanisms regulate channel openness in response to physiological cues, including transjunctional voltage differences that close the pore at potentials exceeding 50 mV, as well as decreases in intracellular pH or rises in cytosolic Ca²⁺ concentration, which induce conformational changes to block passage.^[39]^[40] Permeability is further modulated post-translationally, notably through phosphorylation of connexins; for instance, protein kinase C (PKC) phosphorylates Cx43 at serine 368, reducing channel conductance and intercellular coupling by altering pore conformation. This regulation allows dynamic adjustment of communication in response to cellular stress or signaling. In cardiac tissue, Cx43 gap junctions ensure electrical synchrony among cardiomyocytes, including pacemaker cells, by propagating action potentials rapidly across the myocardium to coordinate contractions.^[41]^[42] In the liver, connexin 32 (Cx32) forms gap junctions in hepatocytes that support metabolic coordination, such as synchronized glucose output in response to hormonal stimuli, enhancing overall hepatic function. Similarly, in brain astrocytes, connexin-based gap junctions (primarily Cx43) enable the redistribution of energy metabolites like glucose and lactate, buffering metabolic demands during neuronal activity. Unlike plasmodesmata in plants, which traverse cell walls, gap junctions in animals directly link cytoplasms without such barriers.^[43]^[44] Humans express 21 distinct connexin genes, allowing for the formation of homomeric, heteromeric, or heterotypic channels with varied biophysical properties, such as differing permeabilities and gating sensitivities, which contribute to tissue-specific functions.^[45]

Plasmodesmata

Plasmodesmata are specialized intercellular channels unique to plant cells that penetrate the cell walls, establishing cytoplasmic continuity between adjacent cells and enabling symplastic transport of molecules. These structures function analogously to gap junctions in animals by allowing the exchange of ions, metabolites, and signaling molecules, but they incorporate an extension of the endoplasmic reticulum and traverse rigid cellulosic walls.^[46]^[47] The core structure of a plasmodesma consists of a narrow cytoplasmic sleeve, known as the annulus, bounded by the plasma membrane on the outer side and a central desmotubule—an appressed extension of the endoplasmic reticulum—on the inner side. The overall pore diameter typically ranges from 20 to 50 nm, with the desmotubule measuring 15 to 20 nm in diameter, allowing the passage of small molecules and proteins up to approximately 50 kDa depending on the size exclusion limit. Plasmodesmata exhibit structural variations, including simple forms with a single channel and complex, branched types (such as Y- or H-shaped) that connect multiple cells, particularly in specialized tissues like sieve elements of the phloem. Their density varies across plant tissues, typically ranging from 1 to 15 plasmodesmata per square micrometer of cell wall.^[48]^[49]^[47]^[50]^[51] Plasmodesmata assemble primarily during cytokinesis through the fusion of the cell plate, where endoplasmic reticulum strands become trapped and encased by forming cell wall material, generating simple primary plasmodesmata. Secondary plasmodesmata form de novo in existing walls after cell division, often as branched structures during cell expansion or in response to developmental needs, such as in phloem sieve elements where complex branching facilitates efficient transport. This assembly process relies on tethering proteins like synaptotagmins and VAP27 that position the endoplasmic reticulum at plasma membrane contact sites.^[50]^[52]^[49]^[53] Regulation of plasmodesmatal permeability occurs through dynamic mechanisms that adjust the aperture size to control transport. Callose, a β-1,3-glucan polysaccharide, deposits at the neck regions of plasmodesmata, narrowing the pores and reducing the plasmodesmal index—the proportion of open channels—via synthesis by callose synthases and degradation by β-1,3-glucanases. Additionally, the actin-myosin cytoskeleton modulates dilation by forming filaments that spiral around the desmotubule, influencing permeability through myosin-driven movements and actin bundling. These controls allow plants to fine-tune intercellular trafficking in response to environmental or developmental cues.^[54]^[49]^[54] In plants, plasmodesmata play essential roles in resource allocation and coordination, particularly by facilitating the symplastic distribution of nutrients such as sucrose from phloem sieve elements to sink tissues like growing fruits or roots. They also mediate signaling by transporting hormones like auxin, which directs patterning and tropisms, and proteins such as florigen, which regulates flowering time across long distances. These functions support coordinated growth and stress responses in compact plant tissues.^[55]^[56]^[57] Plasmodesmata are evolutionarily unique to plants and their green algal ancestors, emerging with the transition to multicellularity to enable symplastic integration in cellulosic tissues without reliance on extracellular matrix-based junctions found in animals. Phylogenetic evidence indicates their origin in charophyte algae, with increased complexity and regulatory mechanisms evolving in land plants over 400 million years ago to support terrestrial adaptation and compact tissue organization.^[58]^[58]^[46]

Occluding Junctions

Tight Junctions

Tight junctions, also known as zonula occludens, are specialized occluding junctions that encircle the apical region of epithelial and endothelial cells, forming a continuous seal that regulates the paracellular pathway for ions, solutes, and water across tissue barriers.^[59] These junctions create a selective barrier by restricting diffusion between the apical and basolateral membrane domains while allowing controlled transport based on molecular size and charge.^[60] The structure of tight junctions consists of intricate, strand-like networks composed primarily of claudin family proteins, such as claudin-1 which promotes barrier formation, and occludin, embedded as tetraspan transmembrane proteins in the plasma membranes of adjacent cells.^[61] The extracellular loops of these proteins, particularly claudins, interact in a zipper-like manner across neighboring cells, forming selective paracellular pores with an effective size cutoff of approximately 0.4 nm radius, allowing passage of small ions while restricting larger solutes and preventing unregulated paracellular leakage.^[62] Assembly begins with the recruitment of intracellular scaffolding proteins ZO-1, ZO-2, and ZO-3, which organize the transmembrane components into a stable scaffold, while junctional adhesion molecules (JAMs) enhance initial cell-cell adhesion during junction formation.^[63] Tight junctions display variable permeability profiles, classified as "tight" with minimal leakage in tissues requiring stringent barriers, such as the blood-brain barrier, or "leaky" with selective ion permeability in absorptive epithelia, such as the kidney proximal tubule; this is quantified by transepithelial electrical resistance (TER), where tight junctions exhibit TER values exceeding 1000 Ω·cm².^[64] In the blood-brain barrier, claudin-5 predominates, contributing to its exceptionally low permeability by forming charge-repulsive seals that block paracellular passage of small molecules.^[65] Conversely, in the intestinal epithelium, tight junctions modulate nutrient absorption by permitting limited paracellular flux of ions and small solutes while restricting larger molecules.^[66] Dynamic regulation of tight junctions occurs during processes like epithelial polarization, exemplified by the calcium switch mechanism, where depletion of extracellular calcium disrupts junctions and repletion triggers rapid reassembly through cadherin-mediated adhesion and actin cytoskeleton reorganization.^[67] This process ensures adaptability to developmental or environmental cues, with extensions to tricellular junctions providing complete sealing at cell vertices.^[68]

Tricellular Junctions

Tricellular junctions form specialized seals at the vertices where three epithelial cells converge, distinct from the linear strands of bicellular tight junctions. These structures were first identified in the 1970s using freeze-fracture electron microscopy, which revealed unique configurations of junctional strands at cell corners, such as single fibril models in amphibian epidermis and particle aggregates in other epithelia. The core structure of tricellular junctions consists of central sealing elements formed by tricellulin, a tetraspan protein related to occludin, which localizes specifically at these tricellular contacts (TCs). Angulins, including angulin-1 (also known as lipolysis-stimulated lipoprotein receptor, LSR), angulin-2 (ILDR1), and angulin-3 (ILDR2), are single-pass transmembrane proteins that anchor tricellulin at TCs through interactions with its cytoplasmic tail, recruiting claudins to form a barrier plug that fills the central tube of approximately 10 nm diameter where bicellular tight junction strands converge. This plug-like organization contrasts with the continuous, anastomosing strands of bicellular junctions, providing a robust seal at the tricellular vertex, with typically one such central element per TC.^[69]^[70]^[71] Assembly of tricellular junctions begins with angulins establishing initial contacts at nascent TCs, followed by tricellulin recruitment and claudin polymerization to complete the barrier. Disruptions in this process, such as reduced angulin-1 expression or altered tricellulin localization, compromise gut epithelial integrity, contributing to increased paracellular permeability observed in inflammatory bowel diseases like Crohn's disease. These junctions are particularly essential in high-resistance epithelia, such as the gallbladder, where they enhance overall barrier function by sealing vulnerable corner regions. Tricellular junctions integrate with the broader tight junction network to maintain epithelial impermeability.^[70]00390-X/fulltext)^[71] In invertebrates, tricellular junctions exhibit analogous structures to vertebrate forms but are associated with septate junctions, which serve similar paracellular barrier roles; for instance, in Drosophila epithelia, specialized tricellular septate junctions involve proteins like Mesh to seal vertices and prevent solute leakage.^[70]

Molecular Components

Transmembrane Adhesion Molecules

Transmembrane adhesion molecules are integral membrane proteins that span the plasma membrane and facilitate direct cell-cell or cell-extracellular matrix (ECM) interactions essential for junctional stability in various cell junctions. These proteins typically feature extracellular domains for ligand binding, a single transmembrane helix, and intracellular tails that can interact with cytoplasmic components. In adherens junctions and desmosomes, they mediate homophilic or heterophilic adhesion, while in hemidesmosomes, they anchor cells to the basal lamina.^[72] The cadherin superfamily represents the primary mediators of calcium-dependent cell-cell adhesion across multiple junction types. Classical cadherins, such as E-cadherin, N-cadherin, and P-cadherin, predominate in adherens junctions, where they engage in homophilic binding facilitated by extracellular cadherin (EC) domains that form zipper-like structures upon Ca²⁺ binding, which rigidifies the ectodomain and promotes cis- and trans-dimerization.^[73] In desmosomes, desmosomal cadherins including desmogleins (Dsg1-4) and desmocollins (Dsc1-3) perform analogous Ca²⁺-dependent homophilic interactions, contributing to tissue integrity in mechanically stressed epithelia.^[74] These interactions are highly specific, with EC1-EC5 domains orchestrating adhesion strength and specificity. Biophysical studies reveal that individual cadherin bonds exhibit rupture forces on the order of 20-150 pN, depending on the cadherin type and loading rate, enabling junctions to withstand tensile stresses.^[75] The integrin family, particularly the α6β4 heterodimer, serves as the key transmembrane component in hemidesmosomes, binding ECM ligands such as laminin-332 in the basement membrane to anchor epithelial cells. Unlike cadherins, integrins mediate heterophilic adhesion and support bidirectional signaling, where extracellular ligand binding triggers intracellular kinase activation to regulate cell motility and survival, while cytoplasmic signals modulate integrin affinity.^[76] This α6β4 integrin is unique among integrins for its association with keratin filaments rather than actin, enhancing stable adhesion in stratified epithelia.^[77] Other transmembrane adhesion molecules include nectins, immunoglobulin-like proteins that initiate adherens junctions through homophilic and heterophilic interactions, recruiting classical cadherins for maturation; junctional adhesion molecules (JAMs), which provide weak homophilic adhesion in tight junctions to support paracellular barrier integrity.^[78]^[79] Post-translational modifications, notably N-glycosylation, modulate cadherin function by altering ectodomain conformation and binding kinetics, with aberrant glycosylation in cancer cells reducing adhesion specificity and promoting metastasis.^[80] These molecules often link briefly to intracellular scaffolds like catenins to transmit forces.^[81]

Intracellular Linking Proteins

Intracellular linking proteins are cytoplasmic components that anchor transmembrane adhesion molecules to the cytoskeleton, thereby providing structural integrity to cell junctions. These proteins facilitate mechanical force transmission and signaling by bridging the plasma membrane to actin filaments, intermediate filaments, or microtubules. Key families include the Armadillo proteins, which primarily associate with adherens junctions and desmosomes, and the Plakin proteins, which connect to intermediate filaments in desmosomes and hemidesmosomes. Scaffold proteins further organize junctional complexes by recruiting additional effectors. The Armadillo family, characterized by armadillo repeat domains, plays a central role in linking cadherins to the actin cytoskeleton at adherens junctions. β-Catenin binds directly to the cytoplasmic tail of cadherins and recruits α-catenin, which in turn interacts with actin filaments to reinforce cell-cell adhesion.^[82] Plakoglobin, a paralog of β-catenin, serves a dual role in both desmosomes and adherens junctions, where it associates with desmosomal cadherins in desmosomes and classical cadherins in adherens junctions, contributing to plaque assembly and cytoskeletal anchorage.^[83] p120-Catenin stabilizes cadherins by binding to their juxtamembrane domain, preventing endocytosis and promoting surface retention essential for junction maintenance.^[84] Quantitative analyses underscore the abundance of catenins in stabilizing these structures.^[19] The Plakin family consists of large cytolinker proteins that primarily tether intermediate filaments to junctional plaques. Desmoplakin is a core component of desmosomes and hemidesmosomes, where its C-terminal domain binds keratin intermediate filaments, enabling robust mechanical coupling in epithelial and cardiac tissues.^[85] Plectin, versatile in its associations, links intermediate filaments and microtubules to hemidesmosomes via interactions with integrin β4, supporting epithelial attachment to the extracellular matrix.^[86] Envoplakin, prominent in epidermal desmosomes, contributes to plaque reinforcement and intermediate filament anchorage, particularly during keratinocyte differentiation.^[87] Scaffold proteins organize junctional components through modular domains, enhancing stability and signaling. In tight junctions, ZO-1, ZO-2, and ZO-3 utilize PDZ domains to bind the C-termini of claudins and occludin, recruiting actin and other effectors to form a peripheral scaffold.^[88] Afadin, at adherens junctions, links nectins to the actin cytoskeleton via its F-actin-binding domain, facilitating initial adhesion and coordination with cadherin complexes.^[89] Junctional dynamics are regulated by post-translational modifications, such as phosphorylation of catenins by Src and Abl kinases, which disrupts cytoskeletal links and promotes epithelial-to-mesenchymal transition (EMT). For instance, Src-mediated tyrosine phosphorylation of β-catenin reduces its affinity for cadherins, leading to junction disassembly and increased cell motility during EMT.^[90] Abl similarly phosphorylates β-catenin at planar junctions, altering its localization and contributing to cytoskeletal reorganization.^[91]

Channel-Forming Proteins

Channel-forming proteins are integral membrane proteins that assemble into pores enabling direct intercellular exchange of ions, metabolites, and signaling molecules in communicating junctions such as gap junctions and plasmodesmata. In animals, these primarily include connexins and pannexins, which oligomerize into hemichannels that dock to form complete channels, while in plants, specialized proteins like plasmodesmata-located proteins (PDLPs) contribute to channel regulation.^[92]^[93]^[94] Connexins constitute a family of 21 isoforms in humans, each exhibiting tissue-specific expression and functional properties; for instance, connexin 32 (Cx32) predominates in liver hepatocytes, while connexin 45 (Cx45) is prominent in cardiac and vascular tissues.^[93] Each connexin monomer features a characteristic four-pass transmembrane topology, with four alpha-helical domains (M1–M4) that line the central aqueous pore, flanked by two extracellular loops, an intracellular loop, and N- and C-terminal cytoplasmic tails. Six monomers assemble into a hemichannel (connexon), and docking of two hemichannels from adjacent cells forms the gap junction channel, with the transmembrane domains creating a selective pore approximately 1.5 nm in diameter that permits passage of molecules up to ~1 kDa. Recent cryo-EM structures of Cx43 gap junctions, resolved at 2.26 Å resolution, reveal details of the pore architecture and gating mechanisms.^[95] Docking compatibility is governed by specific residues in the extracellular loops, allowing heterotypic channels such as Cx43/Cx45 pairs in vascular endothelium, where compatibility ensures functional intercellular coupling despite isoform differences.^[92]^[96]^[36] Pannexins, a related family of three isoforms in mammals (Panx1–3), form hexameric hemichannels that function independently or as unpaired pores, often releasing ATP and other nucleotides into the extracellular space to mediate paracrine signaling. Unlike connexins, pannexin channels exhibit larger pores, estimated at up to 4–5 nm in diameter, allowing permeation of larger molecules such as ATP (molecular weight ~507 Da) and dyes like Lucifer yellow, with reduced selectivity compared to the more size- and charge-discriminating connexin pores. Panx1, the most studied isoform, predominantly localizes to neuronal and glial cells, where its hemichannels open under pathological conditions like ischemia to facilitate ATP efflux.^[97]^[98]^[99] In plants, plasmodesmata serve as analogous channels for symplastic transport, and proteins such as plasmodesmata-located proteins (PDLPs), a family of eight receptor-like transmembrane proteins in Arabidopsis, localize to these structures to regulate aperture size and permeability. PDLPs interact with callose synthases and hydrolases to modulate the deposition of callose, a β-1,3-glucan that narrows plasmodesmal necks and restricts molecular flux, thereby controlling intercellular trafficking of nutrients and signals. For example, PDLP5 promotes callose accumulation at plasmodesmata during pathogen defense, dynamically adjusting channel openness without forming the pore itself.^[100]^[94]^[101] Gating of channel-forming proteins maintains controlled permeability, with connexin-based gap junctions exhibiting sensitivity to transjunctional voltage (V_j), the potential difference across the channel; for many isoforms like Cx43, V_j gradients exceeding 50–100 mV induce conformational changes that close the pore, preventing electrical uncoupling during membrane depolarization. Chemical gating further modulates openness, as intracellular inositol 1,4,5-trisphosphate (IP3) binds to the C-terminal domain of certain connexins (e.g., Cx32), promoting channel closure in response to calcium waves. Pannexin channels display similar voltage sensitivity but are more responsive to extracellular ATP and mechanical stress, while PDLP-mediated regulation in plasmodesmata relies on enzymatic callose dynamics rather than direct voltage or ligand gating.^[102]^[103]^[104] Turnover of these proteins ensures dynamic regulation of junctional communication, with connexins exhibiting a remarkably short half-life of 1.5–5 hours in most cell types, far shorter than typical membrane proteins. Degradation involves ubiquitination, where E3 ligases target lysine residues on the C-terminus (e.g., in Cx43), marking proteins for proteasomal or lysosomal pathways, including autophagic engulfment of entire gap junction plaques. This rapid cycling allows cells to adjust channel density in response to signaling cues, such as growth factors that accelerate ubiquitination and internalization. Pannexins show comparable turnover rates, though less studied, while plant PDLPs exhibit longer stability tied to developmental stages.^[105]^[106]^[107]

Functions

Mechanical Coupling

Cell junctions, particularly anchoring types such as adherens junctions and desmosomes, play a crucial role in force transduction by transmitting actomyosin-generated tension between adjacent cells. These structures allow epithelial cells to sense and respond to mechanical forces, with measurements indicating that the endogenous tension at cell-cell contacts can reach approximately 100 nN per cell pair, directed perpendicular to the interface and concentrated at contact edges.^[108] This force transmission is quantified using traction force microscopy, which reveals how actomyosin contractility pulls on junctional complexes to maintain tissue integrity under stress.^[108] Adherens junctions, as key anchoring structures, facilitate this process by linking the actin cytoskeleton across cells.^[109] At the tissue level, mechanical coupling via these junctions enables coordinated behaviors such as collective cell migration during wound healing, where cells move as a cohesive sheet while transmitting forces to guide rearward cells.^[110] In the skin, desmosomes specifically resist high shear and tensile forces, preventing epidermal blistering by anchoring intermediate filaments that distribute mechanical load across multiple cells.^[111] Hemidesmosomes further integrate this coupling with the extracellular matrix by stably anchoring basal epithelial cells to the basement membrane, thereby preventing tissue delamination under mechanical strain.^[112] Biophysical models describe cell junctions as viscoelastic springs that exhibit both elastic and viscous properties, allowing them to absorb and transmit forces over time. These models assign a stiffness modulus to junctional components, such as E-cadherin complexes, on the order of 1-2 kPa, enabling tissues to adapt to dynamic loads without rupture.^[113] A prominent example of mechanical coupling is found in cardiomyocytes, where intercalated discs containing desmosomes and adherens junctions synchronize contraction forces, ensuring efficient heart muscle function by distributing tension across the myocardium.^[114]

Intercellular Communication

Cell junctions play a crucial role in intercellular communication by enabling the direct and indirect exchange of signals and metabolites between adjacent cells. Gap junctions facilitate direct exchange through channels that allow the propagation of calcium (Ca²⁺) waves, which coordinate cellular responses such as vasomotor control in vascular smooth muscle cells. These waves typically propagate at speeds of 10–50 μm/s, enabling rapid synchronization across cell networks.^[115] Indirect signaling pathways are modulated by adherens and tight junctions, which integrate mechanical cues with biochemical signals to regulate cellular behavior. Adherens junctions transduce the Wnt/β-catenin pathway, where β-catenin stabilization promotes transcriptional activity driving cell proliferation in developmental and homeostatic contexts. Tight junctions contribute to apicobasal polarity, compartmentalizing signaling molecules and facilitating localized activation of protein kinase C (PKC), which regulates junction assembly and downstream responses.30547-0)00278-5)30262-X) In plants, plasmodesmata serve as symplastic pathways for intercellular communication, allowing the transport of hormones like auxin to establish concentration gradients essential for tropic responses such as phototropism. Regulated gating of plasmodesmata ensures precise auxin distribution, directing asymmetric growth toward light stimuli.00735-1) The temporal and spatial dynamics of junction-mediated communication vary by mechanism: electrical coupling via gap junctions occurs in less than 1 ms, supporting near-instantaneous signal relay, while metabolic diffusion extends over several cell diameters, limited by molecular size and junction permeability. Feedback mechanisms further refine this communication, as signals like transforming growth factor-β (TGF-β) induce junction remodeling during pathological processes such as fibrosis, altering connectivity to propagate profibrotic responses.^[116]81282-9)^[117]00851-6)

Barrier Functions

Occluding junctions, particularly tight and tricellular junctions, establish selective barriers that regulate paracellular permeability across epithelial and endothelial tissues. These structures create charge- and size-selective filters that prevent uncontrolled solute leakage while permitting regulated transport. For instance, in cation-selective epithelia, claudin-2 forms paracellular pores approximately 0.8 nm in diameter, facilitating the passage of small monovalent cations like Na⁺ while restricting larger or anionic molecules.^[118] This selectivity arises from electrostatic interactions within the pore, ensuring that only appropriately charged ions traverse the barrier efficiently.^[119] In various tissues, these barriers fulfill critical protective roles. In the intestinal epithelium, tight junctions inhibit bacterial translocation by limiting the paracellular passage of microbes and endotoxins, thereby preserving gut homeostasis and preventing systemic inflammation.^[120] The glomerular filtration barrier in the kidney, incorporating tight junction-like elements in podocytes, restricts filtration of larger plasma proteins such as albumin (66 kDa), with an effective size cutoff for neutral molecules around 30–70 kDa, maintaining plasma protein levels and averting urinary protein loss.^[121] Similarly, in the corneal epithelium, tight junctions restrict ion and water flux, averting stromal swelling and ensuring optical clarity by countering osmotic imbalances.^[122] Transepithelial transport is facilitated through these barriers via paracellular routes, particularly in leaky epithelia where ion diffusion supports overall flux. For example, Na⁺ conductance across tight junctions typically ranges from 10 to 100 mS/cm², enabling efficient reabsorption in proximal tubules without compromising barrier integrity.^[123] The paracellular pathway comprises two distinct components: the pore pathway, which handles high-capacity, selective ion flux, and the leak pathway, a low-capacity route for larger solutes during stress; these are differentiated experimentally using dilution potential assays that measure charge selectivity and permeability shifts.^[124] These barriers play a vital homeostatic role by sustaining osmotic gradients and pH balance across compartments. By restricting water and ion movement, tight junctions prevent fluid accumulation; their disruption, as seen in inflammatory conditions, leads to edema through unchecked paracellular leakage and osmotic disequilibrium.^[125] In the brain, for instance, tight junction breakdown in the blood-brain barrier exacerbates vasogenic edema by allowing protein-rich fluid extravasation, underscoring their essential function in fluid homeostasis.^[126]

Regulation and Disease

Developmental Regulation

Cell junctions undergo precise temporal and spatial regulation during embryogenesis and tissue differentiation, ensuring proper tissue architecture and compartmentalization. In epithelial tissues, adherens junctions and tight junctions typically assemble shortly after cytokinesis, with adherens junctions forming first to mediate initial cell-cell adhesion via cadherins, followed by tight junctions that seal the paracellular space. Desmosomes, in contrast, mature later during processes like epidermal stratification, providing additional mechanical strength as tissues thicken and differentiate. This sequential assembly is critical for establishing polarized epithelia in early development. Key signaling pathways orchestrate junction formation and remodeling. Rho GTPases, particularly Cdc42, initiate tight junction assembly by recruiting proteins to the apical membrane and promoting actomyosin contractility. The Wnt pathway stabilizes adherens junctions by enhancing cadherin-catenin complex integrity and inhibiting disassembly during morphogenetic movements. During epithelial-to-mesenchymal transition (EMT), transcription factors such as Snail repress junctional components, downregulating E-cadherin and disrupting adherens junctions to facilitate cell migration in gastrulation and neural crest delamination. Junctions play pivotal morphogenetic roles in patterning and synchronization. In Drosophila embryogenesis, septate junctions help define parasegmental compartments during segmentation by restricting diffusion and maintaining signaling gradients. Gap junctions synchronize calcium oscillations and gene expression in somitogenesis, coordinating somite boundary formation across the presomitic mesoderm in vertebrates. In plants, plasmodesmata—cytoplasmic channels analogous to animal gap junctions—are regulated by HD-ZIP IV transcription factors, which control their density and permeability to pattern leaf venation and trichome distribution during vegetative development. Junction maturation generally occurs over 1-2 hours following initial contact, involving cytoskeletal remodeling and protein trafficking. Disruptions in these developmental processes contribute to congenital anomalies, such as neural tube defects arising from impaired junctional integrity in neural epithelium closure.

Pathological Implications

Defects in cell junctions contribute to various pathological conditions, particularly autoimmune diseases where autoantibodies target junctional components. In pemphigus vulgaris, an autoimmune blistering disorder, IgG autoantibodies primarily against desmoglein 3 (and desmoglein 1 in mucosal-sparing variants) bind to the extracellular domains of these desmosomal cadherins, inducing steric hindrance that disrupts keratinocyte adhesion and triggers intracellular signaling pathways such as p38MAPK and PLC/Ca²⁺, leading to acantholysis and intraepidermal blister formation.^[127] Similarly, bullous pemphigoid involves autoantibodies targeting hemidesmosomal proteins BP180 (collagen XVII) and BP230, which activate complement and inflammatory cascades, resulting in subepidermal separation and tense skin blisters through loss of dermal-epidermal attachment.^[128] In cancer, dysregulation of adherens junctions plays a pivotal role in tumor progression and dissemination. Loss or downregulation of E-cadherin, a key transmembrane component of adherens junctions, occurs in the majority of invasive epithelial tumors and promotes epithelial-to-mesenchymal transition (EMT), enhancing cell motility, invasion, and metastasis by releasing β-catenin for transcriptional activation of pro-metastatic genes like Twist.^[129] In gliomas, upregulation of claudin-4 promotes mesenchymal transition and enhances tumor cell proliferation, migration, invasion, and survival.^[130] Genetic mutations in junctional proteins underlie inherited disorders affecting tissue integrity. Arrhythmogenic right ventricular cardiomyopathy (ARVC) arises from mutations in desmoplakin, an intracellular linker in desmosomes, which impair cardiomyocyte adhesion and lead to fibrofatty replacement of the right ventricular myocardium, increasing arrhythmia risk and sudden cardiac death.^[131] In Charcot-Marie-Tooth disease (X-linked form), mutations in connexin 32 disrupt gap junction function in Schwann cells, impairing myelin maintenance and intercellular communication in peripheral nerves, resulting in progressive demyelination, sensory loss, and motor weakness.^[132] Infectious agents exploit junctional vulnerabilities to facilitate tissue invasion. For instance, Clostridium perfringens enterotoxin binds to claudins in tight junctions of intestinal epithelia, disrupting paracellular barriers and enabling bacterial translocation across the gut mucosa, which promotes enteritis and systemic spread.^[133] Therapeutic strategies targeting cell junctions show promise for treating junction-related pathologies. In inflammatory bowel disease (IBD), agents targeting immune cell trafficking aim to reduce infiltration and preserve epithelial barrier integrity by mitigating tight junction disruption in the inflamed colon. Emerging preclinical and early-stage research on cadherin modulators, such as N-cadherin antagonists and E-cadherin activating antibodies, shows promise for stabilizing junctions to limit barrier dysfunction and inflammation in ulcerative colitis models, and inhibit metastasis in cancer.^[134]^[135]

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The E-cadherin stiffness is a constant: k = 1.5 kPa (30,31,32). As expected, the structure of the junction is mainly determined by two dimensionless parameters: ...
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The intercalated disc: a unique organelle for electromechanical ...
The intercalated disc (ID) is a highly specialized structure that connects cardiomyocytes via mechanical and electrical junctions.
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The pericyte connectome: spatial precision of neurovascular ...
Jun 16, 2020 · This GJ-mediated coupling was essential for the fast propagation of a Ca2+ wave leading to a vasomotor response along the vascular branch.Missing: speed | Show results with:speed
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Gap junctions desynchronize a neural circuit to stabilize insect flight
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WNK1 collaborates with TGF-β in endothelial cell junction ... - PNAS
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Claudin-2-mediated cation and water transport share a common pore
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Molecular Basis for Cation Selectivity in Claudin-2–based ... - NIH
Claudin-2 pores were found to be narrow, fluid filled, and cation selective. Charge selectivity was mediated by the electrostatic interaction of partially ...
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Slit Diaphragms Contain Tight Junction Proteins - PMC - NIH
Rat slit diaphragms contain tight junction proteins JAM-A, occludin, and cingulin, despite lacking typical tight junction features.Results · Occludin Is Also Present At... · Tight Junctions Proteins Are...
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The ocular surface epithelial barrier and other mechanisms of ... - NIH
In corneal epithelium, the resistance barrier is primarily provided by the tight junctions [6,7]. Desmosomes, which are abundant in the wing cell layers of ...
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Measurement of paracellular epithelial conductivity by ... - PubMed
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Tight Junction Pore and Leak Pathways: A Dynamic Duo - PMC
The tight junction is composed of at least two functionally distinct pathways: a high-capacity, charge-selective pore pathway that allows passage of small ions ...
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Molecular pathophysiology of cerebral edema - PMC
... tight junctions that collectively form the “physical barrier” of the BBB. Notably ... osmotic gradient that drives water influx and causes cell swelling.
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Molecular Mechanisms of Ischemic Cerebral Edema
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Mechanisms Causing Acantholysis in Pemphigus-Lessons from ...
PV is caused by autoantibodies which primarily target Dsg1 and Dsg3 (8–10). It is characterized by suprabasal splitting in the epidermis and/or oral epithelia.
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The Autoimmune Skin Disease Bullous Pemphigoid - Frontiers
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Loss of E-Cadherin Promotes Metastasis via Multiple Downstream ...
May 15, 2008 · These findings indicate that E-cadherin loss in tumors contributes to metastatic dissemination by inducing wide-ranging transcriptional and functional changes.
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TGF-β induces GBM mesenchymal transition through upregulation ...
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Tight junctional protein family, Claudins in cancer ... - PubMed Central
When tumor cells undergo EMT, tight junctions are dismantled. ... Aberrant expression of claudin-6 contributes to malignant potentials and drug resistance of ...
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Connexin32 and X-linked Charcot-Marie-Tooth disease - PubMed
Mutations in the gap junction gene connexin32 (Cx32) cause the X-linked form of Charcot-Marie-Tooth disease, an inherited demyelinating neuropathy.
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Disruption of Claudin-Made Tight Junction Barriers by Clostridium ...
Mar 5, 2022 · CpE binds to claudins at or near tight junctions in the gut and disrupts their barrier function, potentially by disabling their assembly or via cell signaling ...
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Eldelumab [Anti-IP-10] Induction Therapy for Ulcerative Colitis
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Potential Therapeutic Applications of N-Cadherin Antagonists and ...
This is the only N-cadherin antagonist to enter clinical trials to date. The use of ADH-1 as an anti-cancer therapeutic is discussed in more detail below.
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Full article: E-cadherin activating antibodies limit barrier dysfunction ...
Aug 17, 2021 · Mouse E-cadherin activating antibody treatment reduced inflammation progression in spontaneous IL10-/- model of ulcerative colitis. To test the ...