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Cell adhesion

Cell adhesion is the process by which cells form physical contacts with neighboring cells or the extracellular matrix through specialized protein complexes, enabling the assembly of multicellular organisms into structured tissues.^[1] This fundamental biological phenomenon is mediated by a diverse array of cell adhesion molecules (CAMs), including cadherins for cell-cell interactions and integrins for cell-matrix binding, which facilitate homophilic (like-to-like) or heterophilic (unlike-to-unlike) binding to establish stable junctions.^[2] These interactions are essential for tissue morphogenesis, maintaining structural integrity, and coordinating cellular behaviors such as migration, proliferation, and differentiation during embryonic development and adult homeostasis.^[3] Cell adhesion occurs through two primary categories: cell-cell adhesion, which involves junctions like adherens junctions (anchored by cadherins and catenins) and desmosomes (reinforced by desmogleins and desmocollins), and cell-extracellular matrix (ECM) adhesion, primarily via focal adhesions where integrins link the cytoskeleton to ECM components such as fibronectin and collagen.^[3] These adhesions not only provide mechanical stability but also serve as signaling hubs for mechanotransduction, where physical forces from actomyosin contractility regulate adhesion dynamics, protein recruitment (e.g., talin and vinculin to integrins), and downstream pathways influencing gene expression and cell fate.^[3] Dysregulation of cell adhesion contributes to pathological conditions, including cancer metastasis—where reduced adhesion enables epithelial-to-mesenchymal transition—and developmental disorders like epilepsy linked to protocadherin mutations.^[2] Recent structural studies have elucidated how adhesion proteins form lattice-like or zipper configurations to achieve specificity and strength, advancing therapeutic strategies targeting adhesion in regenerative medicine and oncology.^[2]

Overview and Fundamentals

Definition and Biological Significance

Cell adhesion is the process by which cells form physical contacts with one another or with the extracellular matrix (ECM) through specialized protein complexes, enabling the assembly and maintenance of multicellular structures.^[1] This interaction is mediated by specific adhesion molecules that recognize and bind to complementary receptors or ligands, ensuring stable yet dynamic attachments essential for cellular organization.^[4] Unlike passive sticking, cell adhesion involves regulated molecular recognition that supports tissue integrity and intercellular communication.^[4] Biologically, cell adhesion plays a pivotal role in numerous physiological processes, including embryogenesis, where it facilitates the coordinated migration and sorting of cells to form organized tissues.^[5] It is indispensable for wound healing, as adherent cells collectively migrate to close injuries and restore barrier functions.^[5] In the immune response, adhesion enables leukocytes to adhere to endothelial cells and extravasate into tissues, targeting sites of infection or damage.^[6] Moreover, it underpins tissue architecture by maintaining structural barriers, such as epithelial sheets that separate internal environments from the exterior.^[7] Disruptions in cell adhesion can lead to developmental defects, impaired tissue repair, or pathological conditions.^[8] From an evolutionary perspective, cell adhesion mechanisms emerged as a prerequisite for multicellularity, allowing cells to form stable aggregates and enabling division of labor, specialization, and coordinated behaviors among cells.^[9] This transition likely occurred independently in various eukaryotic lineages, with adhesion providing the foundational step for complex tissue formation.^[9] Key examples illustrate its significance: in epithelial barriers, adhesion maintains impermeability and polarity, preventing leakage and supporting organ function.^[10] During development, it facilitates cell migration, as seen in gastrulation where transient adhesions guide cells to their destinations without compromising collective movement.^[11] Molecules such as cadherins mediate cell-cell adhesion, while integrins handle cell-ECM interactions.^[12]

Historical Background

The study of cell adhesion traces its origins to the 19th century, when advances in light microscopy enabled pathologists like Rudolf Virchow to observe individual cells in close contact within tissues, laying the groundwork for understanding cellular organization in pathological states.^[13] Virchow's work in cellular pathology emphasized that diseases arise from alterations in these cellular units and their arrangements, though the mechanisms of intercellular contacts remained speculative at the time.^[14] The advent of electron microscopy in the 1940s revolutionized the field by revealing ultrastructural details of cell junctions for the first time. Pioneering images from this era, captured by researchers using early transmission electron microscopes, demonstrated distinct membrane specializations where cells abutted, such as dense plaques and intermembrane gaps, indicating specialized adhesion sites rather than mere apposition.^[15] These observations shifted focus from light-level morphology to subcellular architecture, setting the stage for identifying specific junction types. In the 1950s and 1960s, key milestones included Keith Porter's detailed electron microscopic studies of desmosomes in amphibian epidermis, where he described tonofilaments anchoring to dense plaques at cell-cell interfaces, confirming their role in mechanical adhesion without cytoplasmic continuity.^[15] Subsequent work by George Odland and others refined this view, delineating desmosomal substructure—including outer and inner dense plaques—and their prevalence in tissues under mechanical stress, such as skin.^[16] Concurrently, in vitro aggregation assays emerged as experimental tools; these involved dissociating cells with enzymes like trypsin and monitoring re-aggregation under controlled conditions, providing quantitative insights into adhesion dynamics and calcium dependence.^[17] The 1970s and 1980s marked the molecular era, with Masatoshi Takeichi identifying cadherins as calcium-dependent cell-cell adhesion molecules through aggregation assays on teratocarcinoma cells, revealing distinct adhesion systems (e.g., Ca²⁺-dependent vs. independent).^[18] In parallel, Richard Hynes and Erkki Ruoslahti independently discovered integrins in the 1980s as transmembrane receptors mediating cell-matrix adhesion; Hynes named the family after characterizing a common β subunit, while Ruoslahti identified the RGD peptide motif in fibronectin as a key binding site.^[19] These findings, stemming from comparative proteomics of normal and transformed cells, established major adhesion families. From the 1990s onward, conceptual evolution emphasized adhesion's dynamic signaling roles, influenced by advances in cell biology such as the discovery of focal adhesion kinase (FAK) in 1992, which linked integrins to intracellular pathways regulating migration and survival.^[4] This shift from static structural views to integrative functions highlighted how adhesions transduce mechanical and biochemical cues, integrating with broader cellular processes like development and tissue homeostasis. Subsequent decades have seen structural biology advances, such as cryo-electron microscopy revelations of cadherin and integrin complexes as of 2023, further elucidating adhesion mechanics.^[17]^[2]

Molecular Components

Key Adhesion Molecules

Cell adhesion is mediated primarily by a set of transmembrane and secreted proteins known as cell adhesion molecules (CAMs), which can be classified into several major families based on their structure and function. These include cadherins for stable cell-cell interactions, integrins for cell-extracellular matrix (ECM) binding, selectins for transient leukocyte rolling, and the immunoglobulin superfamily (IgSF) for diverse cell-cell recognitions, alongside other molecules like mucins and syndecans that contribute to adhesion and signaling.^[20]^[21] Cadherins form a superfamily of calcium-dependent transmembrane glycoproteins that primarily facilitate homophilic cell-cell adhesion, essential for tissue morphogenesis and maintenance. Classical cadherins, such as E-cadherin (epithelial), N-cadherin (neural), and P-cadherin (placental), feature an extracellular region with five tandem cadherin (EC) domains that mediate Ca²⁺-dependent dimerization between adjacent cells, a cytoplasmic tail that binds catenins for cytoskeletal linkage, and a single transmembrane domain. Non-classical cadherins, like protocadherins, lack strong catenin binding but contribute to neural recognition and synaptic specificity through diverse isoform expression. Cadherins' adhesive strength relies on cis and trans interactions of their EC1 domains, modulated by extracellular Ca²⁺ concentrations.^[22]^[23]^[24] Integrins are heterodimeric transmembrane receptors composed of α and β subunits that bridge the ECM and intracellular cytoskeleton, enabling cell migration, signaling, and mechanotransduction. In mammals, 18 α and 8 β subunits form at least 24 distinct integrins, with combinations like α5β1 binding fibronectin via an RGD motif and αVβ3 interacting with vitronectin. Integrins exist in low-affinity (bent) and high-affinity (extended) conformations, regulated by inside-out signaling through their cytoplasmic tails, which connect to talin and kindlin for activation. Ligand binding triggers outside-in signaling, clustering integrins into focal adhesions.^[25]^[26]^[27] Selectins constitute a family of lectin-like C-type lectins that mediate transient, calcium-dependent cell-cell interactions, particularly in leukocyte recruitment during inflammation. The three members—L-selectin (expressed on leukocytes), E-selectin (endothelial), and P-selectin (endothelial and platelets)—each have an N-terminal C-type lectin domain that binds fucosylated carbohydrate ligands like sialyl Lewis X (sLeX) on glycoproteins. These interactions enable initial tethering and rolling of leukocytes on vascular endothelium under shear flow, with bond lifetimes on the order of milliseconds to facilitate capture before firmer adhesion by integrins. Selectin expression is rapidly upregulated by inflammatory cytokines or thrombin.^[28]^[29]^[30] Immunoglobulin superfamily (IgSF) members are a diverse group of cell surface glycoproteins characterized by one or more immunoglobulin-like (Ig-like) extracellular domains, promoting homophilic or heterophilic cell-cell adhesion in immune, neural, and epithelial contexts. Key examples include neural cell adhesion molecule (NCAM), which supports neurite outgrowth via polysialylated isoforms, and intercellular adhesion molecule-1 (ICAM-1), which binds integrins on leukocytes to stabilize endothelial interactions. IgSF proteins like vascular cell adhesion molecule-1 (VCAM-1) also engage integrins for immune cell recruitment. Their adhesive functions often involve Ig domain-mediated dimerization, with roles in development and immune surveillance.^[31]^[32]^[33] Other notable adhesion molecules include mucins, heavily O-glycosylated transmembrane or secreted proteins that provide a protective glycocalyx layer while modulating adhesion through carbohydrate interactions, as seen in MUC1 binding selectins in cancer metastasis. Syndecans, a family of four transmembrane heparan sulfate proteoglycans, link cells to ECM components like fibronectin and growth factors via their glycosaminoglycan chains and core protein domains, facilitating adhesion and signaling in development and wound healing. These molecules often cooperate with core receptors like integrins for enhanced adhesion.^[34]^[35]^[36]

Associated Proteins and Cytoskeleton Links

Cell adhesion molecules such as cadherins and integrins are anchored to the cytoskeleton through a network of intracellular accessory proteins that provide mechanical stability and enable force transmission across junctions. These linker proteins not only physically couple transmembrane receptors to actin filaments or intermediate filaments but also contribute to the dynamic regulation of adhesion strength under mechanical stress.^[37] In adherens junctions, catenins serve as critical connectors between cadherins and the actin cytoskeleton. β-catenin binds directly to the cytoplasmic tail of cadherins and recruits α-catenin, which in turn interacts with F-actin to stabilize the junctional complex. α-catenin undergoes force-dependent conformational changes that promote actin polymerization and bundling, enhancing junction integrity. p120-catenin associates with the juxtamembrane domain of cadherins, preventing their endocytosis and regulating actin dynamics through interactions with Rho GTPases. These catenins collectively ensure adherens junction stability by integrating adhesion with cytoskeletal tension.^[38]^[39]^[40] Desmosomes and hemidesmosomes rely on plakin family proteins to anchor intermediate filaments, providing robust mechanical resistance in tissues under shear stress. Desmoplakin, a core desmosomal plakin, links desmosomal cadherins via armadillo proteins like plakoglobin to intermediate filaments such as keratins, forming a resilient scaffold essential for epithelial integrity. In hemidesmosomes, plectin—a versatile plakin—bridges integrin β4 tails to intermediate filaments, facilitating attachment to the basement membrane and distributing tensile forces. These proteins' modular structures allow multi-domain interactions that reinforce cytoskeletal networks against deformation.^[41]^[42]^[43] Focal adhesions in cell-matrix interactions are mediated by talin and vinculin, which activate and link integrins to actin. Talin, a large rod-like protein, binds the β-integrin cytoplasmic tail and unfolds under force to expose vinculin-binding sites, simultaneously recruiting F-actin for force transmission. Vinculin, once activated by talin, further strengthens the linkage by binding actin and other focal adhesion components, promoting cluster maturation. Kindlins cooperate with talin as integrin co-activators by stabilizing the open conformation of integrin tails, while integrin-linked kinase (ILK) bridges kindlin and β1-integrins to actin, integrating structural support with signaling pathways like Akt activation. These interactions enable focal adhesions to sense and respond to extracellular stiffness.^[44]^[45]^[46]^[47]^[48] Mechanical models describe how force modulates these links, particularly through catch bonds in integrins that prolong adhesion lifetime under tension, unlike slip bonds that weaken. The Bell model quantifies force-dependent dissociation rates for slip bonds, predicting an exponential increase in off-rate with applied force:

k_{\off} = k_0 \exp\left( \frac{f x_\beta}{k_B T} \right)

where k_{\off} is the dissociation rate, k_0 is the zero-force rate, f is the force, x_\beta is the distance to the transition state, k_B is Boltzmann's constant, and T is temperature. This framework has been extended to catch-slip transitions to explain reinforcement in adhesions like integrin-ECM bonds, where initial force stabilizes the complex before eventual rupture.^[49]^[50]^[51]

Mechanisms in Animal Cells

Cell-Cell Adhesion Structures

Cell-cell adhesion structures in animal tissues primarily consist of specialized junctions that mediate intercellular cohesion, communication, and mechanical integrity. These structures are essential for maintaining tissue architecture, enabling coordinated cellular behaviors during development and homeostasis, and responding to physiological stresses. In epithelial and endothelial tissues, they form a tiered organization along the lateral plasma membranes, with distinct types fulfilling complementary roles in barrier formation, force transmission, and signaling relay. Adherens junctions appear as belt-like bands encircling the apical-lateral regions of cells, linking adjacent cells through connections to the actin cytoskeleton. They play critical roles in tissue morphogenesis by facilitating cell shape changes and collective migration, as well as contributing to barrier function by stabilizing epithelial sheets against mechanical disruption.^[52]^[53]^[54] Desmosomes form discrete, spot-like plaques distributed along the lateral membranes of cells, anchoring intermediate filaments across the intercellular space to provide robust tensile strength. These structures are particularly prominent in mechanically stressed tissues such as the epidermis and cardiac muscle, where they resist shear forces and prevent tissue tearing during contraction or friction.^[52]^[53]^[54] Tight junctions create seal-like occlusions at the most apical contacts between cells, effectively sealing the paracellular pathway and delineating apical from basolateral membrane domains. They regulate the selective permeability of epithelial and endothelial barriers, maintaining tissue polarity and preventing uncontrolled leakage of solutes and fluids, as seen in the blood-brain barrier.^[52]^[53]^[54] Gap junctions establish direct cytoplasmic continuity through arrays of intercellular channels, permitting the diffusion of ions, metabolites, and small signaling molecules between coupled cells. Located throughout various tissues, they enable synchronized activities, such as electrical coupling in cardiac muscle for coordinated contractions or metabolic coupling in astrocytes.^[52]^[53]^[54] Beyond these stable junctions, transient cell-cell adhesions facilitate dynamic interactions in processes like immune surveillance and neural connectivity. Selectin-mediated adhesions promote the rolling of leukocytes along vascular endothelium during inflammation, enabling initial capture and subsequent firm attachment. Members of the immunoglobulin superfamily (IgSF) support specialized contacts, such as in synaptic junctions between neurons or immunological synapses between T cells and antigen-presenting cells.^[55]^[56]^[57] Collectively, these adhesion structures integrate to form cohesive epithelial monolayers or multilayered stratified tissues, with tight and adherens junctions providing apical sealing and circumferential reinforcement, desmosomes adding spot-wise durability, and gap junctions ensuring functional coupling. This hierarchical assembly supports the transition from simple sheets to complex organs, adapting to diverse mechanical and signaling demands across tissue types.^[52]^[53]^[54]

Cell-Matrix Adhesion Structures

Cell-matrix adhesion structures are specialized junctions that anchor animal cells to the extracellular matrix (ECM), facilitating mechanical stability, signal transduction, and cellular responses to environmental cues. These structures primarily involve integrins as transmembrane receptors that bind ECM components such as fibronectin, collagen, and laminin, linking the ECM to the intracellular cytoskeleton. In contrast to cell-cell adhesions, they emphasize interactions with the non-cellular matrix for processes like tissue integrity and motility.^[58] Focal adhesions represent dynamic, actin-linked adhesion sites typically formed at the basal surfaces of motile cells, such as fibroblasts, where they mature into elongated fibrillar adhesions. They consist of over 60 proteins, including integrins (e.g., α5β1 and αvβ3), talin, vinculin, focal adhesion kinase (FAK), and paxillin, which cluster upon ECM binding to form a multi-protein scaffold connecting to F-actin stress fibers. These structures sense substrate stiffness through integrin clustering and force-dependent conformational changes in proteins like talin, enabling mechanotransduction via pathways involving FAK phosphorylation and Rho GTPases. In fibroblasts, focal adhesions drive contractile forces for wound healing and tissue remodeling, with their size and density increasing on stiffer substrates (e.g., from 4 kPa to 32 kPa).^[58]^[59]^[60] Hemidesmosomes provide stable anchorage in epithelial tissues, particularly at basal layers, by linking intermediate filaments to the basement membrane. They feature a tripartite architecture with inner and outer plaques flanking a less dense zone, composed of integrin α6β4, plectin isoform 1a, BPAG1e (BP230), BPAG2 (type XVII collagen), and tetraspanin CD151. Integrin α6β4 binds laminin-332 in the ECM, while plectin and BPAG1e anchor keratin filaments intracellularly, ensuring long-term stability through self-association and phosphorylation regulation. In the epidermis, hemidesmosomes in basal keratinocytes prevent blistering by maintaining adhesion to the dermal-epidermal junction, with disruptions leading to conditions like epidermolysis bullosa.^[61] Other matrix contacts include fibronectin fibrils and invadopodia, which support specialized motility. Fibronectin fibrils form through cell-dependent polymerization, where α5β1 integrins translocate bound fibronectin along actin filaments to create fibrillar adhesions that stabilize the ECM and recruit proteins like tensin. These fibrils are essential for matrix assembly and cell spreading, with their absence causing a 65% loss of ECM integrity within hours. Invadopodia, actin-rich protrusions in invasive cancer cells (0.5–2 µm wide, >2 µm long), concentrate proteases like MT1-MMP at ECM contacts for degradation, facilitating invasion while integrating with nearby focal adhesions via β1 integrins. They enable durotaxis, the stiffness-directed migration where cells move toward rigid substrates (e.g., via asymmetric myosin distribution and FA tugging forces).^[62]^[63]^[59] The dynamics of these structures involve rapid assembly and disassembly cycles critical for cell spreading and invasion. Focal adhesions assemble via initial integrin-ECM engagement and Rac/Rho signaling, maturing over minutes to hours before disassembly through calpain-mediated proteolysis or microtubule targeting. Hemidesmosomes exhibit greater stability but can disassemble under growth factor stimulation (e.g., via PKC-α phosphorylation of β4 integrin). In motile cells, invadopodia turnover is regulated by Src and cortactin, allowing repeated ECM probing during durotaxis. These cycles link briefly to cytoskeletal elements like actin and intermediate filaments for force transmission.^[58]^[61]^[63]

Adhesion in Non-Animal Organisms

Eukaryotic Variations

In plants, cell adhesion primarily occurs through the cell wall and middle lamella, where pectins form the structural basis for intercellular binding. The middle lamella, enriched with homogalacturonan pectins, facilitates adhesion via calcium-mediated cross-links between negatively charged carboxyl groups on pectin chains, providing mechanical strength and tissue cohesion.^[64]^[65] These calcium bridges are dynamically regulated by pectin methylesterases, which demethylate pectins to enable cross-linking and influence wall porosity.^[66] Complementing this apoplastic adhesion, plasmodesmata serve as symplastic channels that connect the cytoplasm of adjacent cells, allowing transport of nutrients, signals, and macromolecules; these structures are functionally analogous to animal gap junctions but traverse the cell wall.^[67] Fungi exhibit adhesion mechanisms adapted to their filamentous growth and environmental interactions, particularly through proteins at hyphal tips and spores. Hydrophobins, small secreted cysteine-rich proteins, self-assemble into amphipathic films at hydrophobic-hydrophilic interfaces, enabling hyphal attachment to surfaces and facilitating aerial hypha formation.^[68]^[69] Agglutinins, such as lectin-like proteins, contribute to hyphal tip adhesion by binding carbohydrate ligands on host surfaces or other fungal cells, promoting colony expansion.^[70] In pathogenic fungi like Candida albicans, spore attachment relies on cell wall adhesins that mediate initial binding to host epithelia, initiating infection through hydrophobic interactions and ligand-specific recognition.^[71]^[72] Protists display diverse adhesion strategies suited to their often motile or parasitic lifestyles. In amoeboid protists such as Amoeba proteus, movement and substrate adhesion depend on dynamic actin-based structures, where F-actin networks form temporary adhesions that drive pseudopod protrusion and retraction without stable focal contacts.^[73]^[74] Parasitic protists like Plasmodium species employ micronemal proteins, including P36 and P52, which are secreted during host cell invasion to form adhesive complexes that facilitate gliding motility and tight junction formation with the target membrane.^[75]^[76] Evolutionarily, non-animal eukaryotic adhesion diverges from animal junction-mediated systems by emphasizing wall-mediated or surface-anchored mechanisms, reflecting adaptations to rigid extracellular matrices or free-living habits. Unlike animals, which rely on integrin-based adhesions, plants and fungi lack integrins but utilize GPI-anchored proteins as adhesins; these glycosylphosphatidylinositol-linked glycoproteins tether to the plasma membrane and cell wall, enabling ligand binding in fungi and some protists.^[9]^[77] This wall-centric approach supports multicellularity in plants via pectin matrices and in fungi via chitin-glucan scaffolds, contrasting with the flexible, cytoskeleton-linked junctions in metazoans.^[78] These adaptations underpin key functional roles in non-animal eukaryotes. In plants, pectin-mediated adhesion guides pollen tube growth along stylar transmitting tracts, where cell wall interactions ensure directed navigation to ovules for fertilization.^[79]^[80] In fungi, adhesins like hydrophobins and agglutinins drive biofilm formation by promoting initial attachment and hyphal aggregation on substrates, enhancing survival in hostile environments such as host tissues.^[81]^[82]

Prokaryotic and Viral Adhesion

In prokaryotes, cell adhesion primarily facilitates colonization, biofilm formation, and pathogenesis through specialized surface structures rather than stable intercellular junctions. Bacterial pili and fimbriae are key appendages that mediate host attachment; for instance, type 1 pili in Escherichia coli are tipped with the FimH adhesin, a mannose-specific lectin that binds to glycoprotein receptors on host epithelial cells, enabling uropathogenic strains to adhere to urinary tract surfaces.^[83]^[84] This interaction is enhanced under shear stress via a catch-bond mechanism, where binding affinity increases with applied force, promoting stable attachment during infection.^[84] Complementing these, curli fibers—amyloid-like protein aggregates produced by enteric bacteria such as E. coli and Salmonella—contribute to adhesion in biofilms by forming extracellular matrices that tether cells to abiotic surfaces and each other, facilitating community aggregation and resistance to environmental stresses.^[85]^[86] Additional prokaryotic mechanisms enhance surface stability and aggregation. S-layer proteins form paracrystalline lattices enveloping many bacterial cells, providing structural integrity and mediating initial adhesion to host tissues or environmental substrates through electrostatic and hydrophobic interactions.^[87]^[88] Exopolysaccharides (EPS), polymeric carbohydrates secreted by bacteria, play a crucial role in quorum sensing-dependent aggregation; these molecules create a hydrated matrix that promotes cell-to-cell adhesion and biofilm maturation, as seen in species like Pseudomonas aeruginosa where EPS production is upregulated by autoinducer signals to coordinate community behavior.^[89]^[90] Viral adhesion, particularly in enveloped viruses, relies on glycoprotein spikes for receptor recognition and subsequent membrane fusion. The SARS-CoV-2 spike protein, for example, binds with high affinity to the angiotensin-converting enzyme 2 (ACE2) receptor on host cells, initiating attachment through its receptor-binding domain.^[91]^[92] In broader terms, enveloped viruses employ class I or II fusion proteins—such as hemagglutinin in influenza or the envelope glycoprotein in HIV—that, following receptor engagement, undergo conformational changes to drive viral-host membrane adhesion and fusion, delivering the viral genome into the cytoplasm.^[93]^[94] These adhesion strategies underpin pathogenic processes. In bacteria, structures like pili enable colonization of host tissues; streptococci, for instance, use surface adhesins to bind damaged heart valves, promoting vegetation formation in infective endocarditis.^[95]^[96] For viruses, attachment often culminates in receptor-mediated endocytosis, where receptor-ligand complexes are internalized via clathrin-coated pits, allowing endosomal acidification to trigger fusion and uncoating, as observed in many RNA viruses including coronaviruses.^[97]^[98] Prokaryotic and viral adhesions differ fundamentally from those in eukaryotes by being predominantly transient and independent of cytoskeletal anchoring, lacking the dynamic remodeling seen in cadherin- or integrin-based junctions.^[85]^[93] Instead, they frequently involve lectin-carbohydrate interactions, such as FimH-mannose binding, which prioritize reversible attachment for rapid colonization over long-term structural integration.^[83]^[84]

Regulation and Dynamics

Intracellular Signaling and Regulation

Cell adhesion initiates a cascade of intracellular signaling events that regulate adhesion strength, cytoskeletal dynamics, and cellular responses such as migration and survival. Upon engagement of adhesion molecules like integrins and cadherins, focal adhesion kinase (FAK) is autophosphorylated at tyrosine 397, creating a docking site for downstream effectors including Src family kinases, which amplify signals to modulate adhesion maturation and turnover.^[99] These pathways form feedback loops that fine-tune adhesion dynamics, ensuring cells adapt to mechanical cues from the extracellular environment. Rho GTPases play a central role in linking adhesion sites to cytoskeletal remodeling. Cdc42 and Rac1 promote the formation of lamellipodia at nascent focal adhesions by driving actin polymerization, while RhoA induces stress fiber assembly and contractility through myosin II activation.^[100] Their activation is mediated by FAK phosphorylation, which recruits guanine nucleotide exchange factors (GEFs) to switch GTPases from inactive GDP-bound to active GTP-bound states, thereby reinforcing adhesion complexes.^[101] Integrin engagement also activates MAPK and PI3K pathways to promote cell survival and prevent anoikis, a form of apoptosis triggered by loss of adhesion. The PI3K/Akt cascade inhibits pro-apoptotic proteins like Bad, while MAPK/ERK signaling enhances proliferation and migration, both downstream of integrin-FAK complexes.^[102] In parallel, cadherin-catenin complexes at cell-cell junctions sequester β-catenin, inhibiting its nuclear translocation and suppressing Wnt/β-catenin target gene expression to maintain epithelial integrity.^[103] Calcium influx and phosphorylation events further regulate adhesion stability. Cadherin-mediated adhesion triggers Ca²⁺ entry, which stabilizes cadherin extracellular domains and promotes junctional assembly by enhancing actin linkage via catenins.^[104] Tyrosine kinases like Src modulate integrin affinity by phosphorylating the β-integrin tail, shifting integrins from low- to high-affinity states for ligand binding and strengthening focal adhesions.^[105] Feedback mechanisms govern adhesion maturation through models like the molecular clutch, where talin and vinculin act as force-sensitive clutches linking actin retrograde flow to integrin clusters; slippage occurs at low forces, but clutch engagement at higher forces matures adhesions into stable focal adhesions.^[106] Signaling kinetics, such as FAK activation by upstream kinases, follow Michaelis-Menten enzyme kinetics, described by the equation:

v = \frac{V_{\max} [S]}{K_m + [S]}

where v is the reaction velocity, V_{\max} is the maximum rate, [S] is substrate concentration, and K_m is the Michaelis constant, reflecting saturation of FAK autophosphorylation under sustained adhesion signals.^[107] Adhesion also influences gene expression via epigenetic regulation through YAP/TAZ mechanotransduction. Mechanical forces at adhesions activate YAP/TAZ by inhibiting their Hippo pathway phosphorylation, allowing nuclear translocation and co-activation of TEAD transcription factors to drive genes involved in proliferation and matrix remodeling.^[108] This pathway integrates adhesion-derived tension to sustain long-term cellular adaptations.^[109]

Environmental and Pathological Influences

The stiffness of the extracellular matrix (ECM) profoundly impacts focal adhesion assembly and cellular differentiation. On soft ECM substrates mimicking brain tissue (approximately 0.1–1 kPa), mesenchymal stem cells (MSCs) form smaller focal adhesions with reduced actin stress fibers, favoring neuronal lineage commitment, whereas stiffer matrices (30–40 kPa, akin to bone) promote larger focal adhesions, increased contractility, and osteogenic differentiation. This mechanosensitive response arises from integrin-ECM interactions that transmit forces to the cytoskeleton, modulating downstream signaling for lineage specification.^[110]^[111] ECM composition, particularly collagen density, further tunes integrin clustering and adhesion dynamics. Higher collagen densities enhance β1-integrin clustering in fibroblasts and cancer cells, stabilizing focal adhesions and amplifying invasive signaling through pathways like FAK and PI3K. In contrast, sparse collagen reduces cluster size and impairs force transmission, limiting cell migration on compliant substrates.^[112]^[113] Soluble environmental factors, including growth factors and biomechanical cues, dynamically alter adhesion molecule expression and junction stability. Transforming growth factor-β (TGF-β) upregulates N-cadherin in epithelial and stromal cells, shifting cell-cell interactions toward mesenchymal phenotypes and enhancing motility. In vascular endothelium, physiological laminar shear stress (10–20 dyn/cm²) reinforces adherens junctions by reorganizing VE-cadherin and cortical actin, whereas oscillatory or low shear promotes junction disassembly and barrier leakage.^[114]^[115] Pathological conditions and toxins disrupt adhesion integrity through targeted molecular interference. Hypoxia, common in ischemic tissues, weakens tight junctions by downregulating tight junction proteins, increasing paracellular permeability in epithelial barriers.^[116] Inflammatory cytokines like TNF-α reduce E-cadherin surface expression in endothelial and epithelial cells, destabilizing adherens junctions and facilitating epithelial-mesenchymal transition (EMT). Aging drives ECM remodeling toward fibrosis, with collagen crosslinking elevating stiffness and perpetuating aberrant integrin signaling in organs like the lung and liver. Environmental toxins, such as cadmium, disrupt cadherin-based cell-cell adhesions at low doses (1–10 μM), compromising desmosomal stability and epithelial integrity.^[117]^[118]^[119] Ligand-induced changes in adhesion strength often exhibit cooperative dose-responses, modeled by the Hill equation:

\theta = \frac{[L]^n}{K_d + [L]^n}

Here, \theta represents fractional receptor occupancy (correlating to adhesion force), [L] is ligand concentration, K_d the dissociation constant, and n the Hill coefficient (>1 for positive cooperativity, as seen in integrin αLβ2 activation where multivalent ligands amplify binding avidity). This nonlinearity ensures robust adhesion thresholds in variable microenvironments.^[120]

Applications and Implications

Clinical Disorders and Diseases

Cell adhesion defects underlie a range of clinical disorders, primarily affecting skin integrity, immune function, hemostasis, and gastrointestinal barrier maintenance, as well as contributing to cancer progression. These conditions often result from genetic mutations or autoimmune responses targeting adhesion molecules, leading to impaired intercellular or cell-matrix interactions. Diagnosis typically involves genetic testing, immunological assays, and histopathological examination to assess junction integrity and molecular defects. Pemphigus vulgaris is an autoimmune blistering disorder of the skin and mucous membranes caused by IgG autoantibodies targeting desmoglein 3 (Dsg3), with additional involvement of desmoglein 1 (Dsg1) in cutaneous lesions, resulting in loss of keratinocyte adhesion and intraepidermal blister formation.^[121] These autoantibodies disrupt desmosomal junctions, inducing acantholysis and fragile blisters that erode to form painful ulcers.^[122] Hereditary diffuse gastric cancer (HDGC) arises from germline mutations in the CDH1 gene encoding E-cadherin, a key cadherin in adherens junctions, leading to loss of cell-cell adhesion in gastric epithelium and development of invasive signet ring cell carcinomas.^[123] CDH1 mutations impair E-cadherin function, promoting early-onset diffuse gastric tumors with high penetrance, often requiring prophylactic gastrectomy in carriers.^[124] Integrin-related disorders include Glanzmann thrombasthenia, a rare autosomal recessive bleeding disorder caused by mutations in ITGA2B or ITGB3 genes, resulting in deficient or dysfunctional αIIbβ3 integrin on platelets, which prevents fibrinogen binding and impairs platelet aggregation during hemostasis.^[125] Affected individuals experience mucocutaneous bleeding and prolonged bleeding times due to failure of platelet plug formation.^[126] Leukocyte adhesion deficiency (LAD) type I stems from mutations in the ITGB2 gene encoding the β2 integrin subunit (CD18), leading to absent or reduced β2 integrins (e.g., LFA-1) on leukocytes, which disrupts firm adhesion to endothelium and impairs neutrophil migration to infection sites, causing recurrent bacterial infections and delayed wound healing.^[127] LAD type II involves defective fucosylation of selectin ligands like sialyl Lewis X due to mutations in the GDP-fucose transporter gene SLC35C1, hindering leukocyte rolling and tethering, resulting in similar infectious complications with additional developmental abnormalities such as the Bombay blood phenotype.^[128] Junctional diseases encompass epidermolysis bullosa (EB), a group of inherited mechanobullous disorders where mutations in genes encoding hemidesmosome components, such as COL17A1 (type XVII collagen) or LAMA3/LAMB3/LAMC2 (laminin-332), weaken dermal-epidermal adhesion, causing skin fragility and blistering upon minor trauma.^[129] In junctional EB subtypes, these mutations disrupt anchoring filaments in hemidesmosomes, leading to subepidermal separation and chronic wounds prone to secondary infections and scarring.^[130] Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, features tight junction dysfunction with increased paracellular permeability ("leaky gut") due to downregulation or mislocalization of claudins and occludin, allowing luminal antigens to penetrate the mucosa and trigger chronic inflammation.^[131] This barrier leak contributes to diarrhea, immune activation, and tissue damage in the intestinal epithelium.^[132] In cancer metastasis, epithelial-mesenchymal transition (EMT) plays a pivotal role by downregulating E-cadherin expression through transcriptional repressors like Snail and Twist, enabling epithelial tumor cells to lose cell-cell adhesion, gain migratory mesenchymal traits, and invade surrounding tissues.^[133] E-cadherin loss facilitates dissemination and establishment of distant metastases in carcinomas such as breast and colorectal cancers.^[134] Vascular endothelial (VE)-cadherin, critical for endothelial adherens junctions, regulates angiogenesis in tumors; its disruption or soluble forms promote vascular permeability and sprouting, supporting metastatic spread by enhancing nutrient supply to tumor cells.^[135] Prevalence of these disorders varies: pemphigus vulgaris affects approximately 1-5 per 100,000 individuals, Glanzmann thrombasthenia 1 in 1,000,000, LAD 1 in 100,000, junctional EB approximately 1 in 2 million, and HDGC in familial clusters with 30-50% lifetime gastric cancer risk in CDH1 carriers.^[123]^[125] IBD has a prevalence of 0.3-0.5% in Western populations.^[131] Diagnostics include genetic screening via next-generation sequencing for mutations in CDH1, ITGB2, or hemidesmosome genes, confirming hereditary cases like HDGC or EB.^[136] Immunological assays detect anti-desmoglein antibodies in pemphigus, while flow cytometry assesses integrin expression in LAD.^[127] Skin or mucosal biopsies evaluate junction integrity through immunofluorescence for adhesion proteins or electron microscopy for ultrastructural defects in EB and pemphigus.^[137] In IBD, endoscopic biopsies with immunohistochemistry assess tight junction protein localization to quantify barrier dysfunction.^[138]

Research and Therapeutic Advances

Anti-adhesion therapies targeting integrins have emerged as a key strategy in treating inflammatory and neoplastic diseases. Natalizumab, a monoclonal antibody against the α4 integrin subunit, blocks leukocyte adhesion to vascular endothelium, significantly reducing relapse rates in relapsing-remitting multiple sclerosis by inhibiting immune cell trafficking across the blood-brain barrier.^[139] Similarly, vedolizumab, targeting the α4β7 integrin, has shown efficacy in inflammatory bowel disease by selectively preventing gut-specific lymphocyte homing.^[27] These agents highlight the therapeutic potential of modulating cell adhesion to control pathological inflammation, though risks such as progressive multifocal leukoencephalopathy with natalizumab underscore the need for careful monitoring.^[140] In oncology, RGD-mimetic small molecules like cilengitide were developed to disrupt αvβ3 and αvβ5 integrin-mediated tumor cell adhesion to the extracellular matrix, aiming to inhibit angiogenesis and metastasis in glioblastoma. Phase III trials in the 2010s, however, revealed no overall survival benefit, with median survival at 26.3 months comparable to controls, leading to discontinuation and lessons on dose-dependent pro-angiogenic effects at low concentrations that inadvertently promoted tumor growth.^[141] These findings emphasized the complexity of integrin signaling, where partial inhibition can paradoxically enhance vascularization, informing subsequent trial designs to prioritize higher dosing or combination therapies. Emerging targets leverage genetic engineering to enhance adhesion for therapeutic gain. Chimeric antigen receptor (CAR)-T cells have been modified to incorporate adhesion molecules, such as integrins or selectins, to improve infiltration and retention in solid tumors, addressing the poor tumor homing observed in conventional CAR-T therapies.^[142] For instance, engineering CAR-T cells with bispecific ligands targeting both tumor antigens and extracellular matrix components has enhanced tumor targeting in preclinical models of glioblastoma, promoting localized cytotoxicity.^[143] In wound healing, CRISPR/Cas9-mediated editing of cadherins, such as knockout of P-cadherin in intestinal epithelial cells, has accelerated re-epithelialization by reducing cell-cell adhesion barriers and enhancing migration without compromising barrier integrity.^[144] Post-2020 advances have illuminated adhesion dynamics through advanced technologies. Single-cell RNA sequencing has unveiled heterogeneity in adhesion molecule expression within tumor cells, revealing subpopulations with altered integrin profiles that drive metastatic potential in pancreatic ductal adenocarcinoma, enabling identification of adhesion-based therapeutic vulnerabilities.^[145] Artificial intelligence models, integrating computational simulations of cytoskeletal and junctional forces, now predict epithelial junction dynamics and cell intercalation during tissue morphogenesis, offering insights into adhesion-regulated remodeling in development and disease.^[146] Notably, 2023 studies demonstrated that tumor-derived exosomes carrying integrins like α6β4 and β1 promote organ-specific metastasis by priming pre-metastatic niches through enhanced endothelial adhesion and vascular permeability.^[147] As of 2025, the FDA has approved prademagene zamikeracel (Zevaskyn), the first cell-based gene therapy for recessive dystrophic epidermolysis bullosa, correcting COL7A1 mutations to restore type VII collagen and improve dermal-epidermal adhesion, marking a milestone in treating adhesion defects in skin disorders.^[148] Emerging targets include vascular cell adhesion molecule-1 (VCAM-1) for inhibiting leukocyte adhesion in atherosclerosis and cardiovascular disease, and cell adhesion molecule-1 (CADM1) for CAR-T therapies in lung adenocarcinoma.^[149]^[150] Biomaterials mimicking the extracellular matrix have advanced tissue engineering applications. Hydrogels incorporating RGD peptides and tunable stiffness replicate ECM mechanics, supporting cell spreading and differentiation in 3D cultures for regenerative medicine.^[151] These scaffolds have facilitated vascularized bone regeneration by modulating integrin ligation and osteogenic signaling in mesenchymal stem cells.^[152] For stem cell niches, biomaterials with dynamically adjustable adhesion ligands, such as peptide amphiphiles, enable precise control over pluripotency maintenance and directed differentiation, mimicking native niche cues to enhance engraftment in vivo.^[153] Challenges in these approaches include off-target effects, such as unintended disruption of physiological adhesions leading to immunosuppression or bleeding risks in integrin inhibitors.^[139] Future directions emphasize personalized medicine through adhesion profiling via single-cell omics, allowing tailored therapies based on individual tumor adhesion landscapes to minimize adverse events and optimize efficacy.^[145]

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We find that integrin clustering is robust on rigid substrates with high ligand density, but is impaired on substrates that are highly compliant or have low ...
[115]
TGF-β1 induces N-cadherin expression by upregulating Sox9 ... - NIH
We demonstrate that TGF-β1 increased N-cadherin expression, and migratory activity in HSC-4 cells through upregulation of Sox9 expression, and promotion of Sox9 ...
[116]
Transient and Steady-State Effects of Shear Stress on Endothelial ...
We report that shear stress causes partial disassembly of the adherens junction complex, followed by a reassembly that reflected shear-induced reorganization of ...
[117]
Hypoxia disrupts human bronchial epithelial barrier integrity via tight ...
Aug 23, 2025 · Hypoxia modulates the expression of tight junction proteins in human bronchial epithelial cells, disrupts intercellular junctional integrity, ...
[118]
Inflammatory cytokines induce a reduction in E-cadherin expression ...
Inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), induce EMT in human cell lines. However, whether inflammatory ...
[119]
Extracellular matrix as a driver of progressive fibrosis - JCI
Jan 2, 2018 · In this Review, we differentiate fibrosis initiation from progression and focus primarily on progressive lung fibrosis impairing organ function.The ECM as a driver of fibrosis... · ECM composition in... · Modeling ECM...
[120]
Toxic Mechanisms of Five Heavy Metals: Mercury, Lead, Chromium ...
One of the earliest toxic effects of Cd is the disruption of cadherin-mediated cell–cell adhesion. This may cause mild level of oxidative stress. Effect of Cd ...
[121]
and P-selectin-induced intermediate activation of integrin αLβ2 ... - NIH
Cooperativity between selectin and integrin binding was evaluated by dose-response analysis, providing new insight into the signaling mechanism. INTRODUCTION.
[122]
Evaluation of desmoglein 1 and 3 autoantibodies in pemphigus ...
Pemphigus is an autoimmune blistering disease of the skin and mucous membranes caused by autoantibodies against desmoglein 1 (Dsg1) and desmoglein 3 (Dsg3).
[123]
Antibodies against desmoglein 3 (pemphigus vulgaris antigen ... - NIH
IgG autoantibodies against Dsg3 in PNP sera play a pathogenic role in inducing loss of cell adhesion of keratinocytes and causing blister formation.
[124]
CDH1 and hereditary diffuse gastric cancer: a narrative review
Jun 5, 2023 · This review aims to summarize the current understanding of CDH1 and HDGC, highlighting its molecular and cellular implications as well as its clinical ...
[125]
Hereditary Diffuse Gastric Cancer: A 2022 Update - PMC - NIH
Dec 8, 2022 · Mutations in CDH1 gene have been associated with the development of signet ring cell carcinoma in situ (SRCC-pTis), characterized by tumor cells ...
[126]
Glanzmann Thrombasthenia: Perspectives from Clinical Practice on ...
Jun 11, 2021 · Glanzmann thrombasthenia (GT) is a rare inherited bleeding disorder characterized by dysfunctional fibrinogen-mediated platelet aggregation.
[127]
Glanzmann thrombasthenia: genetic basis and clinical correlates - NIH
Glanzmann thrombasthenia (GT) is an autosomal recessive disorder of platelet aggregation caused by quantitative or qualitative defects in integrins αIIb and β3.
[128]
Leukocyte Adhesion Deficiency (first update) - PMC
In LAD-I, mutations are found in ITGB2, the gene that encodes the β subunit of the β2 integrins. This syndrome is characterized directly after birth by delayed ...
[129]
Leukocyte adhesion defect: Where do we stand circa 2019? - PMC
The function of β2 integrin, CD18 is lost in LAD I. LAD II is caused by defective rolling phase which results from defect in post-translational fucosylation.
[130]
Epidermolysis Bullosa - StatPearls - NCBI Bookshelf - NIH
Jan 11, 2024 · ... mutations affect the hemidesmosome and potentially disrupt the keratin cytoskeleton found within basal keratinocytes. Mutated KLHL24 and ...
[131]
Epidermolysis bullosa. I. Molecular genetics of the junctional ... - NIH
Certain subtypes of EB are associated with mutations in specific genes, and examination of the mutation database has revealed general genotype‐phenotype ...
[132]
Tight junctions in inflammatory bowel diseases and ... - NIH
Barrier dysfunction is likely to be caused by epithelial damage including apoptosis, erosion and ulceration that are characteristic of gut inflammation.
[133]
Intestinal Barrier Dysfunction in Inflammatory Bowel Disease
Sep 29, 2023 · This review aims to examine the role of intestinal barrier dysfunction in the development of inflammatory bowel disease
[134]
Epithelial–mesenchymal transition in tumor metastasis - PMC - NIH
The epithelial–mesenchymal transition (EMT) is a developmental program that enables stationary epithelial cells to gain the ability to migrate and invade as ...
[135]
The E-Cadherin and N-Cadherin Switch in Epithelial-to ... - NIH
In this review, we summarized the recent understanding of the roles of E- and N-cadherins in cancer invasion and metastasis as well as the crosstalk with other ...
[136]
VE-Cadherin in Cancer-Associated Angiogenesis - NIH
May 26, 2023 · VM has been correlated with high tumor grade, cancer cell invasion, cancer cell metastasis, and reduced survival of cancer patients.
[137]
E-cadherin genetic screening and clinico-pathologic characteristics ...
Germline CDH1 mutation remain the only germline genetic defect described in this type of patients and CDH1 mutation screening should be recommended for ...Missing: disorders diagnostics
[138]
Epithelial integrity, junctional complexes, and biomarkers associated ...
This review aims to describe the molecular structure of intestinal epithelial tight junction proteins and to characterize their organization and interaction.
[139]
Tight junctions: from molecules to gastrointestinal diseases - NIH
In the intestine, tight junction disruption can cause the leaky gut that is known to be associated with pathogenesis and progression of the gastrointestinal ...
[140]
Emerging therapeutic opportunities for integrin inhibitors - Nature
Sep 17, 2021 · The pan-α4 inhibitor natalizumab (Tysabri) reduces clinical relapses in patients with multiple sclerosis. Natalizumab also reduces the severity ...
[141]
Progressive multifocal leukoencephalopathy and the spectrum of JC ...
most notably natalizumab for multiple sclerosis — have led to a surge of iatrogenic PML. The spectrum of presentations of JCV ...
[142]
Cilengitide: an integrin-targeting arginine-glycine-aspartic acid ... - NIH
In this review we will summarize the rationale and current experience of cilengitide in the treatment of GBM. Preclinical studies confirmed both the importance ...
[143]
CAR-T cell therapy for cancer: current challenges and future directions
Jul 4, 2025 · This review offers an overview of the current development of CAR-T cell therapies for both hematologic and solid tumors, while examining the ...
[144]
P-Cadherin Regulates Intestinal Epithelial Cell Migration and ...
Apr 27, 2022 · Consistently, the CRISPR/Cas9-mediated knockout of P-cadherin in human IEC accelerated epithelial wound healing without affecting cell ...
[145]
Extracellular vesicle-cell adhesion molecules in tumours
Sep 21, 2023 · Exosome-mediated transfer of CD44 from high-metastatic ovarian cancer cells promotes migration and invasion of low-metastatic ovarian cancer ...
[146]
Revisiting the biophysical aspects of extracellular-matrix-mimicking ...
This review critically evaluates hydrogels as ECM mimics for 3D cell cultures. ... tissue engineering and regenerative medicine. Graphical abstract ...Missing: 2020-2025 | Show results with:2020-2025
[147]
ECM-mimicking composite hydrogel for accelerated vascularized ...
This study shows that the multifunctional composite hydrogel of GelMA and DNA can successfully simulate the biological functions of natural bone ECM
[148]
Next-Generation Biomaterials for Culture and Manipulation of Stem ...
Here, strategies to probe and direct stem cell fate through tunable biomaterials are examined. Culture platforms whose properties can be dynamically ...