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Cell adhesion molecule

Cell adhesion molecules (CAMs) are a diverse family of transmembrane glycoproteins expressed on the cell surface that mediate specific interactions between cells (homotypic or heterotypic cell-cell adhesion) or between cells and the extracellular matrix (cell-matrix adhesion), enabling the formation and maintenance of multicellular structures essential for embryonic development, tissue integrity, immune responses, and wound healing.^[1]^[2] These molecules are classified into four major families based on their structural domains and binding mechanisms: the cadherin family, which includes classical cadherins like E-cadherin, N-cadherin, and P-cadherin that form calcium-dependent homophilic bonds via extracellular cadherin repeats; the integrin family, comprising αβ heterodimers that bind extracellular matrix components such as fibronectin and laminin in a cation-dependent manner; the selectin family, consisting of L-, E-, and P-selectins that facilitate transient, calcium-dependent interactions with carbohydrate ligands during processes like leukocyte rolling; and the immunoglobulin superfamily (IgSF), featuring proteins like ICAM-1, VCAM-1, and NCAM with Ig-like domains that support calcium-independent adhesion and signaling.^[1]^[3]^[2] Structurally, CAMs typically span the plasma membrane with extracellular domains for ligand recognition, a single transmembrane helix, and intracellular tails that link to the actin cytoskeleton via adaptor proteins such as catenins (for cadherins) or talin/vinculin (for integrins), allowing them to integrate mechanical forces with intracellular signaling pathways including MAPK, PI3K/Akt, and Rho GTPases.^[1]^[4]^[2] Beyond adhesion, CAMs function as dynamic regulators of cellular behavior by transducing bidirectional signals that influence proliferation, migration, differentiation, and apoptosis; for instance, they modulate epidermal growth factor receptor (EGFR) activity to control cell growth in development and contribute to pathological processes like tumor invasion when dysregulated.^[4]^[2]^[3]

Introduction

Definition and Importance

Cell adhesion molecules (CAMs) are a diverse class of cell surface proteins that mediate specific adhesive interactions between cells, either homotypically (between cells of the same type) or heterotypically (between cells of different types), as well as between cells and the extracellular matrix (ECM).^[1] These proteins are typically transmembrane glycoproteins that bridge the plasma membrane, facilitating both physical attachment and bidirectional signaling between the extracellular environment and the cell interior.^[4] CAMs are fundamental to multicellular organization, enabling the formation and maintenance of tissues by ensuring cells remain properly positioned and connected.^[3] They are indispensable in key biological processes, including embryonic development, where they orchestrate cell migration, sorting, and differentiation to build complex tissue architectures; immune responses, through which they support leukocyte adhesion, rolling, and transmigration to sites of infection; wound healing, by driving cell proliferation, migration, and extracellular matrix remodeling for tissue repair; and neuronal connectivity, where they promote axon guidance, synapse formation, and neural circuit stability.^[4] Disruption of CAM-mediated adhesion can result in severe developmental abnormalities, immune deficiencies, delayed wound closure, and neurological pathologies such as neurodevelopmental disorders.^[5] Beyond structural roles, CAMs contribute to broader cellular homeostasis by transducing mechanical and chemical signals across the membrane, influencing gene expression, proliferation, and survival in response to environmental cues.^[1] This integrative function underscores their importance in sustaining tissue integrity and adaptive responses throughout an organism's lifespan.^[6]

Historical Background

Early observations of cell adhesion date back to the late 19th century, when microscopists like Wilhelm Roux noted the reaggregation of isolated frog embryo blastomeres, proposing "cytotropism" as an attractive force between cells.^[7] In 1907, H.V. Wilson demonstrated that dissociated sponge cells could reaggregate into functional, species-specific structures, highlighting the adhesive properties essential for tissue formation.^[7] By the 1930s and 1940s, Johannes Holtfreter introduced the concept of tissue "affinity," showing that amphibian embryonic cells selectively adhere and self-organize based on their developmental origins, using dissociation techniques to reveal these interactions.^[7] These phenomenological studies laid the groundwork, emphasizing adhesion's role in morphogenesis without identifying molecular mechanisms.^[8] In the 1950s and 1960s, advances in cell culture and enzymology propelled the field forward, particularly through Abraham Moscona's work on tissue dissociation and reaggregation; he developed trypsin-based methods to separate cells and observed their selective resorting, confirming adhesion's specificity in development.^[8] The 1970s marked the transition to molecular identification, with Masatoshi Takeichi discovering calcium-dependent cell-cell adhesion molecules, later termed cadherins, through studies on teratocarcinoma cells that revealed a 150-kDa protein essential for adhesion in 1977.^[9] Concurrently, Gerald Edelman isolated the neural cell adhesion molecule (NCAM), the first member of the immunoglobulin superfamily (IgSF), in 1976, linking it to neural development.^[8] Richard Hynes contributed pivotal insights into cell-matrix adhesion, identifying fibronectin in 1973 and proposing transmembrane linkers by 1976, leading to the cloning of the first integrin subunits in 1986 and the family's naming in 1987.^[10] The 1980s saw the cloning of additional IgSF members and integrins, solidifying their roles in diverse adhesions, while the 1990s brought structural elucidation through X-ray crystallography, such as the 1995 atomic-resolution structure of N-cadherin's amino-terminal domain, revealing homophilic binding interfaces. This era shifted classification from descriptive observations to defined molecular families—IgSF, integrins, cadherins, and selectins—based on shared domains and functions, enabling targeted research in developmental biology.^[8] Pioneers like Takeichi, Hynes, and Edelman drove this evolution, transforming adhesion from a cellular phenomenon to a cornerstone of molecular cell biology.^[11]

Structural Features

General Architecture

Cell adhesion molecules (CAMs) are predominantly single-pass transmembrane proteins characterized by a common topological organization that facilitates intercellular and cell-matrix interactions. The extracellular domain, typically located at the N-terminus, consists of multiple modular structures responsible for ligand binding and specificity, often featuring repeats such as immunoglobulin-like folds. This is connected to the plasma membrane via a single hydrophobic transmembrane helix, approximately 20-25 amino acids long, which anchors the protein and allows for lateral mobility within the lipid bilayer. The C-terminal intracellular tail, varying in length from short peptides to extended domains, interacts with cytoskeletal elements like actin filaments or intermediate filaments, thereby linking adhesion sites to the cellular cytoskeleton for mechanical stability and signal propagation.^[12] Biochemically, most CAMs are glycoproteins, with post-translational modifications such as N- and O-linked glycosylation playing crucial roles in modulating their stability, folding, and interaction properties. Their molecular weights generally range from 50 to 200 kDa, influenced by isoform variations, glycosylation extent, and proteolytic processing, as exemplified by neural CAMs (NCAMs) at 120-180 kDa and integrins at 80-150 kDa. These properties enhance solubility, protect against proteolysis, and contribute to the recognition specificity in diverse physiological contexts.^[13]^[14] The core architecture of CAMs exhibits remarkable evolutionary conservation across metazoans, though origins vary by family: integrins and related components trace to the holozoan ancestor predating the metazoan radiation, with homologs in choanoflagellates and filastereans, while cadherins represent metazoan innovations present in early diverging animals such as sponges and ctenophores. This preservation from invertebrates to vertebrates underscores the ancient origins of adhesion machinery in certain families, enabling the transition to multicellularity through stable cell-cell contacts. While the overall topology remains consistent, sequence divergences have allowed functional adaptations in higher organisms.^[15] Notable variations in this architecture include glycosylphosphatidylinositol (GPI)-anchored forms, which lack a transmembrane domain and are instead tethered to the outer leaflet of the plasma membrane via a lipid anchor, as seen in certain NCAM isoforms and T-cadherin. Additionally, soluble secreted variants exist, derived from alternative splicing or ectodomain shedding, which can modulate adhesion by acting as decoy ligands or bridging molecules without direct membrane integration. These alternatives expand the functional repertoire while retaining core extracellular motifs for binding.^[14]

Key Domains and Motifs

Cell adhesion molecules (CAMs) feature modular extracellular domains that facilitate specific interactions between cells or with the extracellular matrix. Immunoglobulin-like (Ig-like) domains, characterized by a beta-sandwich fold consisting of two antiparallel beta-sheets, are prevalent in many CAMs and mediate homophilic binding, where molecules on adjacent cells interact in a like-with-like manner.^[16] These domains typically span 70-110 amino acids and provide structural stability through disulfide bonds, enabling precise recognition during cell-cell contacts.^[1] Fibronectin type III (FnIII) domains, another common extracellular module, also adopt a beta-sandwich topology but are elongated and often involved in heterophilic interactions with extracellular ligands; they contribute to the tensile strength of adhesion complexes by linking to other domains.^[17] Lectin-like motifs, which include carbohydrate-recognition domains (CRDs), allow CAMs to bind glycosylated surfaces on opposing cells or matrix components, promoting adhesion through sugar-protein interactions without specifying family distinctions.^[18] Calcium-binding sites are integral to the function of certain CAMs, particularly those requiring divalent cations for conformational rigidity and adhesion strength. In calcium-dependent CAMs, specialized motifs—such as sequences of conserved aspartates and glutamates—bind multiple Ca²⁺ ions between adjacent domains, rigidifying the molecule and enabling trans interactions across cell membranes.^[1] These sites integrate with the overall transmembrane setup, where extracellular domains extend from a single-span helical region to position binding interfaces optimally for intercellular engagement.^[16] Intracellular motifs in CAMs link adhesion events to cytoskeletal dynamics and protein recruitment. PDZ-binding motifs, typically short C-terminal sequences like X-S/T-X-Φ (where Φ is a hydrophobic residue), interact with PDZ domains in scaffold proteins such as PSD-95 or syntenin, facilitating the assembly of multiprotein complexes at the plasma membrane.^[19] Tyrosine-based motifs, conforming to the YxxΦ consensus, serve as phosphorylation sites within the cytoplasmic tails; upon activation, these motifs recruit Src homology 2 (SH2) domain-containing kinases, modulating intracellular associations without delving into downstream pathways.^[20] Beyond domains, specific sequence motifs underpin ligand recognition and molecular organization in CAMs. The RGD (Arg-Gly-Asp) tripeptide sequence, found in various extracellular ligands, is a canonical motif recognized by certain CAMs to initiate adhesion, with the aspartate side chain forming key hydrogen bonds in the binding pocket.^[21] Cis-dimerization motifs, often involving small amino acid patterns like Small-X₃-Small in transmembrane helices or extracellular interfaces, promote lateral clustering of CAMs on the same cell surface, enhancing avidity for trans binding partners.^[22]

Classification and Families

Immunoglobulin Superfamily (IgSF) CAMs

The immunoglobulin superfamily (IgSF) of cell adhesion molecules (CAMs) represents the largest and most diverse family of calcium-independent CAMs, characterized by the presence of one or more immunoglobulin-like (Ig-like) domains that mediate cell-cell interactions. These molecules typically feature 2 to 7 extracellular Ig-like domains arranged in a rigid, rod-like architecture, often stabilized by flexible linkers between domains, which allows for precise homophilic or heterophilic binding. Unlike other CAM families, IgSF members do not require calcium ions for adhesion, enabling stable interactions in diverse physiological contexts such as neural development and immune responses.^[16] Structurally, IgSF CAMs are predominantly type I transmembrane proteins, with an extracellular region composed of variable numbers of Ig-like folds—typically β-sandwich structures—that form the basis for molecular recognition. For instance, neural cell adhesion molecule (NCAM) possesses five Ig-like domains, while intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) each have five and seven Ig-like domains, respectively, contributing to their extended, rod-shaped conformations that facilitate multivalent interactions. L1 cell adhesion molecule (L1CAM), another key member, includes six Ig-like domains in its extracellular portion, enabling it to project away from the cell surface for effective engagement with opposing cells. These domains often adopt handshake-like or horseshoe configurations during binding, as revealed by crystallographic studies.^[16]^[23]^[24] Key members of the IgSF CAMs include neural CAMs such as L1CAM and NCAM, which are critical for processes like axon guidance and synaptic adhesion, and intercellular CAMs like ICAM-1 and VCAM-1, which support leukocyte-endothelial interactions in immune contexts. Binding specificity in this family is primarily achieved through interfaces on the Ig-like domains, where homophilic interactions—such as those in NCAM and L1CAM—occur via symmetric or cis-trans engagements between identical molecules, while heterophilic binding, as seen in ICAM-1 with its integrin partners, involves complementary surfaces on distinct Ig domains. Alternative splicing further diversifies these molecules, generating isoforms with varying domain compositions; for example, NCAM produces isoforms (e.g., NCAM-120, NCAM-140, NCAM-180) that differ in cytoplasmic tails and transmembrane properties, modulating adhesion strength and signaling potential.^[16]^[23]^[24]^[25] A distinctive feature of IgSF CAMs is their calcium independence, which contrasts with other CAM families and allows for robust adhesions in calcium-fluctuating environments, such as during neural synapse formation or immune cell trafficking. This property, combined with their modular Ig-domain architecture, enables IgSF members to form ordered assemblies, like the zipper-like arrays observed in NCAM, enhancing avidity in synaptic and immune adhesions without reliance on extracellular cations.^[16]^[23]

Integrins

Integrins are a major family of cell adhesion molecules that primarily mediate cell-extracellular matrix (ECM) interactions through their heterodimeric structure. They consist of non-covalently associated α and β subunits, with 18 distinct α subunits and 8 β subunits identified in humans, forming at least 24 unique integrin heterodimers. Each integrin features a large ectodomain composed of a globular head region responsible for ligand binding and leg-like tail domains that extend toward the cell membrane, connecting to the cytoskeleton via short cytoplasmic tails (except for the longer tail of β4). These structures require divalent cations such as Mg²⁺ or Ca²⁺ for proper conformation and activation, enabling the integrin to transition from a low-affinity bent state to a high-affinity extended state.00971-6)^[26]^[27] Ligand binding by integrins occurs primarily at the globular head, where the α subunit's β-propeller domain and the β subunit's I-like domain recognize specific motifs in ECM proteins. A prominent example is the recognition of the Arg-Gly-Asp (RGD) tripeptide sequence, found in proteins such as fibronectin, vitronectin, and fibrinogen, which facilitates strong adhesion to the ECM. Other ligands, like laminin and collagen, are bound by specific integrins via distinct motifs, such as the GFOGER sequence in collagen IV. This binding is regulated by bidirectional signaling: inside-out signaling, triggered by intracellular cues (e.g., via talin and kindlin binding to the β tail), induces conformational changes that increase ligand affinity, while outside-in signaling propagates from ligand engagement to activate downstream pathways like focal adhesion kinase (FAK) phosphorylation.00971-6)^[26]^[27] Among integrin subtypes, the β1 family is the most versatile, pairing with 12 different α subunits to form receptors like α5β1, which specifically binds fibronectin and plays a key role in cell migration and tissue organization. In contrast, β2 integrins are predominantly expressed on leukocytes, with examples such as αLβ2 (LFA-1) mediating immune cell adhesion to endothelial cells during inflammation. A distinctive feature of integrins is their ability to cluster into focal adhesions upon ligand engagement, forming multiprotein complexes that mechanically couple the ECM to the actin cytoskeleton and transduce signals for cell spreading, proliferation, and survival. This clustering amplifies signaling and distinguishes integrins from other adhesion molecules like those in the immunoglobulin superfamily, which more commonly facilitate cell-cell contacts.00971-6)^[26]^[27]

Cadherins

Cadherins represent a major family of calcium-dependent cell adhesion molecules that mediate homophilic interactions between cells, primarily in epithelial and other tissues, enabling the formation of stable adherens junctions.^[28] These proteins are single-pass transmembrane glycoproteins characterized by their extracellular domains, which facilitate adhesion in a calcium-sensitive manner, contrasting with other adhesion molecules by their specificity for cell-cell rather than cell-matrix contacts.^[29] The structure of classical cadherins features five extracellular cadherin (EC) repeats, denoted EC1 through EC5, each comprising approximately 110 amino acids folded into an immunoglobulin-like beta-sheet structure.^[28] These repeats are connected by linker regions that form calcium-binding pockets, where three Ca²⁺ ions typically bind with varying affinities to rigidify the ectodomain, preventing flexibility and promoting adhesive conformations.^[30] In contrast, atypical cadherins, such as protocadherins, may exhibit more variable numbers of EC repeats (up to 15 or more) and lack the conserved cytoplasmic tail found in classical forms.^[29] Classical cadherins are further subdivided into type I (e.g., E-cadherin, N-cadherin) and type II (e.g., VE-cadherin), distinguished by sequence differences in the EC1 domain that influence binding specificity, with type I showing higher adhesive strength due to conserved histidine-alanine-valine (HAV) motifs.^[31] Cadherin-mediated adhesion occurs through trans-homophilic interactions, where EC1 domains from opposing cells engage in strand-swapping, forming zipper-like dimers that extend laterally to create clustered junctions.^[30] This process is initiated by calcium binding, which stabilizes the ectodomain and exposes the adhesive interface, while cis-dimerization on the same cell surface enhances clustering and avidity without requiring prior trans engagement.^[32] The zipper model posits that multiple trans interactions propagate along the junction, contributing to mechanical strength and force transmission.^[29] Key subtypes include E-cadherin, predominantly expressed in epithelial tissues to maintain tissue integrity via strong adherens junctions; N-cadherin, found in neural and mesenchymal cells, supporting migration and synapse formation; and VE-cadherin, restricted to endothelial cells, where it regulates vascular permeability and barrier function.^[28] These subtypes share the core structural features but differ in tissue-specific expression and minor sequence variations affecting interaction kinetics.^[33] A distinctive feature of cadherins is their cytoplasmic linkage to the actin cytoskeleton via catenins: the conserved tail binds β-catenin and p120-catenin, with β-catenin recruiting α-catenin to indirectly connect to F-actin filaments, thereby coupling adhesion to cytoskeletal dynamics for junction reinforcement.^[29] In epithelial-to-mesenchymal transition (EMT), a "calcium switch" mechanism allows modulation of adhesion; reduced extracellular Ca²⁺ or signaling cues destabilize E-cadherin junctions, promoting N-cadherin upregulation and actin reorganization into migratory stress fibers.^[34] This switch is pivotal in developmental processes and pathology, where loss of calcium-dependent rigidity facilitates junction disassembly.^[30]

Selectins

Selectins constitute a family of cell surface glycoproteins that mediate calcium-dependent adhesion between leukocytes and endothelial cells through interactions with carbohydrate ligands. These type I transmembrane proteins share a conserved modular architecture, consisting of an N-terminal C-type lectin domain (also known as the carbohydrate-recognition domain or CRD), followed by an epidermal growth factor (EGF)-like domain, a varying number of consensus repeats (short consensus repeats or SCRs homologous to complement regulatory proteins), a transmembrane domain, and a short cytoplasmic tail.^[35] The C-type lectin domain is responsible for ligand binding, while the EGF-like domain and consensus repeats contribute to the overall rigidity and presentation of the binding site.^[35] The selectin family comprises three members: E-selectin (CD62E), P-selectin (CD62P), and L-selectin (CD62L), each with distinct numbers of consensus repeats—six for E-selectin, nine for P-selectin, and two for L-selectin—allowing for variations in molecular length and flexibility.^[35] All three exhibit similar three-dimensional topologies in their extracellular domains, enabling analogous ligand recognition despite differences in expression and localization.^[35] Unlike cadherins, which form stable protein-protein junctions, selectins engage in transient, glycan-based interactions that do not require direct protein-protein contacts for initial adhesion.^[35] Selectins bind to sialylated and fucosylated glycan structures, such as sialyl Lewis X (sLe^X, Neu5Acα2-3Galβ1-4[Fucα1-3]GlcNAc) and related determinants, presented on glycoproteins or glycolipids of counter-ligands like P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes or endothelial cells.^[36] This recognition is strictly calcium-dependent, with Ca²⁺ ions coordinating the hydroxyl groups at positions 3 and 4 of the fucose residue in the ligand, stabilized by hydrogen bonds involving conserved tyrosine and glutamate residues in the selectin's lectin domain.^[36] Binding affinities are relatively low, with dissociation constants in the millimolar range for sLe^X and nanomolar for extended ligands like sulfated PSGL-1, facilitating reversible interactions rather than firm attachment.^[35] In contrast to integrins, which promote strong, shear-resistant adhesion often involving extracellular matrix components, selectins specialize in initial, weak contacts without such reinforcement.^[35] Expression patterns of selectins are tailored to their roles in dynamic cellular interactions. E-selectin is not constitutively expressed but is transcriptionally induced on cytokine-activated endothelial cells, appearing on the surface approximately 3-4 hours after stimulation. P-selectin is pre-synthesized and stored in granules—α-granules of platelets and Weibel-Palade bodies of endothelial cells—from where it rapidly translocates to the plasma membrane upon cellular activation, enabling near-immediate responses.^[37] L-selectin, in turn, is constitutively present on the surface of most leukocytes, including naive lymphocytes, monocytes, and neutrophils, but undergoes proteolytic shedding following activation to regulate adhesion.^[38] A hallmark of selectin function is their mediation of leukocyte tethering and rolling along the vascular endothelium under conditions of blood flow shear stress, a process essential for initial capture in immune surveillance and recruitment.^[39] These interactions are characterized by rapid on-off kinetics, allowing cells to roll at velocities of 1-10 μm/s without arresting, thereby distinguishing selectins from mechanisms that enable static or firm adhesion.^[35]

Functions

Adhesion Mechanisms

Cell adhesion molecules (CAMs) mediate physical linkages between cells or between cells and the extracellular matrix (ECM) through homotypic or heterotypic interactions. Homotypic adhesion involves symmetric binding between identical CAMs on opposing cell surfaces, such as cadherin-cadherin interactions that form stable junctions in epithelial tissues.^[16] In contrast, heterotypic adhesion occurs via asymmetric binding between different CAMs or a CAM and its ligand, exemplified by nectin-1 binding to nectin-3, which often yields stronger adhesive forces than homotypic pairs due to specific interface geometries.^[16] These binding modes determine tissue specificity and mechanical stability, with homotypic interactions promoting uniform cell sorting and heterotypic ones enabling diverse cellular communications.^[40] The biophysical properties of CAM bonds underpin their adhesive efficacy, characterized by affinity (intrinsic binding strength of individual molecules) and avidity (cumulative strength from multivalent clustering). Individual CAM-ligand affinities typically range from micromolar to nanomolar dissociation constants, but avidity increases dramatically through lateral clustering in the plasma membrane, enhancing overall bond lifetime and resistance to dissociation under mechanical stress.^[41] For instance, integrin clustering amplifies adhesion to ECM ligands like fibronectin, where multimer formation boosts effective binding by orders of magnitude.^[41] Force-dependent reinforcement further modulates bond dynamics; selectins form catch bonds, where applied tensile force prolongs bond lifetime by stabilizing the complex, facilitating leukocyte rolling on vascular endothelium under shear flow up to an optimal threshold before transitioning to slip bonds.^[42] This mechanism ensures adhesion persists in dynamic fluid environments without requiring constant energy input.^[43] Dynamic regulation of CAM adhesion involves conformational rearrangements and membrane mobility that adapt binding in response to cellular cues. Integrins, for example, undergo extension from a low-affinity bent state to a high-affinity extended-open conformation, increasing ligand affinity over 1000-fold and enabling rapid activation during cell migration.^[44] Lateral mobility within the lipid bilayer allows CAMs to diffuse and cluster at contact sites; in leukocytes, mobile LFA-1 integrin nanoclusters (diffusion coefficient ~0.056 μm²/s) orchestrate microcluster formation for stable adhesion under shear, whereas immobilization disrupts this process.^[45] Cadherins briefly exemplify zipper-like cis interactions that promote trans binding, though full details reside in family-specific architectures.^[16] Environmental factors, particularly ion concentrations, fine-tune CAM function through allosteric modulation. Calcium ions are crucial for many CAMs, rigidifying cadherin ectodomains at junctions between extracellular repeats and stabilizing cis-dimers with a free energy change of approximately -30 kcal/mol, while low calcium induces hinge flexibility and adhesion loss.^[46] Gradients in extracellular calcium, often varying from 1-2 mM in tissues to lower levels during remodeling, thus regulate adhesion onset and disassembly by altering conformational rigidity and binding interfaces.^[46] Such ion-dependent mechanisms ensure context-specific adhesion without intracellular signaling.^[47]

Intracellular Signaling

Cell adhesion molecules (CAMs) transduce extracellular cues into intracellular signals upon ligand binding, initiating cascades that modulate cytoskeletal organization, gene expression, and cell motility. This process involves the recruitment of adaptor proteins and kinases to the cytoplasmic tails of CAMs, leading to phosphorylation events and activation of downstream pathways such as MAPK and PI3K/Akt. In particular, clustering of CAMs at the plasma membrane amplifies these signals, enabling cells to sense and respond to their microenvironment.^[48] Mechanotransduction is a critical aspect of CAM signaling, particularly in integrins, where mechanical forces from the extracellular matrix are transmitted to the cytoskeleton. Talin serves as a primary linker, binding to the β-integrin cytoplasmic tail and extending under tensile force to expose vinculin-binding sites; this recruitment of vinculin strengthens connections to F-actin and myosin, reinforcing focal adhesions and propagating force-dependent signals. This force-induced unfolding of talin acts as a mechanosensitive switch, integrating physical cues with biochemical responses to regulate cell spreading and migration.^[49]^[50]^[48] Kinase activation is central to CAM-mediated signaling, with Src family kinases (SFKs) playing a pivotal role in phosphorylating intracellular motifs. In immunoglobulin superfamily (IgSF) CAMs, such as PECAM-1, ligand-induced clustering leads to SFK-mediated phosphorylation of ITIM motifs, which recruit SH2 domain-containing phosphatases like SHP-1 and SHP-2 to dampen activating signals from co-engaged receptors. Conversely, some IgSF CAMs, including L1, feature ITAM-like sequences that, upon phosphorylation by SFKs like Fyn, activate Syk family kinases and downstream MAPK/ERK pathways, promoting neurite outgrowth and proliferation. Integrin engagement similarly activates SFKs, which phosphorylate FAK to initiate PI3K/Akt and MAPK cascades, enhancing cell survival and motility through clustered adhesion sites.^[51]^[52]^[53]^[26] Crosstalk between different CAM families amplifies and fine-tunes intracellular signaling. Integrins and cadherins cooperate at focal adhesions, where integrin activation promotes cadherin clustering via shared regulators like Rho GTPases and FAK, stabilizing adherens junctions and coordinating force transmission to the actin cytoskeleton. This bidirectional interplay ensures balanced adhesion during epithelial morphogenesis. IgSF CAMs, such as NCAM, link to non-receptor tyrosine kinases like Abl, which phosphorylate cytoskeletal targets to regulate junctional integrity and cell migration, often in concert with integrin signals.^[54]^[55] Negative regulation prevents prolonged signaling and maintains cellular homeostasis. Phosphatases like PTP1B dephosphorylate key adhesion substrates, including β-integrin tails and p130Cas, thereby attenuating SFK and FAK activities to limit focal adhesion turnover and migration. Additionally, endocytosis internalizes activated CAMs, such as integrins and cadherins, trafficking them to endosomes where further dephosphorylation occurs, effectively terminating signals and recycling receptors for reuse.^[56]^[57]^[58]

Roles in Development and Homeostasis

Cell adhesion molecules (CAMs) play pivotal roles in embryonic development by facilitating tissue organization and morphogenetic movements. During gastrulation, cadherins such as C-cadherin in Xenopus embryos mediate tissue elongation and convergence-extension movements essential for proper involution of the mesoderm.^[59] In neurulation, N-cadherin promotes mesenchymal cell condensation in somites, enabling the formation of epithelial-like structures that support neural tube closure.^[59] Cadherin-mediated sorting further drives compartmentalization, where differential expression of cadherins like E-cadherin and N-cadherin causes cells to recognize and segregate into distinct layers, reinforcing tissue boundaries through homophilic adhesion.^[59] These processes integrate CAM signaling with cytoskeletal dynamics to coordinate cell rearrangements during morphogenesis.^[59] In neural development, immunoglobulin superfamily (IgSF) CAMs and integrins guide axon pathfinding by providing both adhesive substrates and instructive signals to growth cones. IgSF CAMs, such as NCAM and L1, mediate homophilic and heterophilic interactions that regulate axon extension, fasciculation, and navigation along specific pathways in the developing nervous system.^[60] Their activation triggers intracellular signaling cascades, including cytoskeletal remodeling via Rho GTPases, which control growth cone motility and directionality.^[60] Integrins complement these functions by linking axons to extracellular matrix components like laminin, stabilizing adhesions and promoting directed outgrowth during target recognition.^[60] CAMs are essential for maintaining tissue homeostasis in adult epithelia and endothelia. E-cadherin, a core component of adherens junctions, ensures epithelial barrier integrity by mediating calcium-dependent cell-cell adhesion, which stabilizes the intestinal epithelium and prevents leakage under basal conditions.^[61] In the intestine, E-cadherin supports crypt-villus architecture and Paneth cell maturation, with its loss leading to disrupted barrier function and epithelial shedding even without inflammation.^[61] Similarly, VE-cadherin maintains vascular homeostasis by forming endothelial adherens junctions that regulate permeability and prevent hemorrhage.^[62] It controls endothelial cytoskeleton organization and gene expression to sustain vessel stability throughout development and adulthood.^[62] In adult physiology, CAMs coordinate wound healing by orchestrating cell migration, proliferation, and tissue remodeling. Integrins such as α5β1 and αvβ6 facilitate keratinocyte and fibroblast movement into the wound bed, promoting re-epithelialization and granulation tissue formation through interactions with fibronectin and latent TGF-β.^[63] Cadherins, including E-cadherin, restore cell-cell contacts post-migration to rebuild epithelial integrity.^[63] In the nervous system, neural cell adhesion molecule (NCAM), particularly its polysialylated form (PSA-NCAM), supports synaptic plasticity by enabling activity-dependent remodeling of hippocampal synapses.^[64] PSA-NCAM expression at synapses is regulated by neuronal activity, and its removal prevents long-term potentiation (LTP) and depression (LTD), while reexpression restores these processes.^[64] Disruption of CAM function highlights their necessity for development and homeostasis, as seen in knockout models. Conditional or global deletion of β1 integrin in mice results in peri-implantation embryonic lethality due to inner cell mass failure, underscoring its role in early blastocyst organization and implantation.^[65]

Pathological Implications

Involvement in Cancer

Cell adhesion molecules (CAMs) play a critical role in cancer progression by facilitating tumor cell detachment, invasion, and dissemination. In epithelial cancers, the loss of cell-cell adhesion is a hallmark event driven by the epithelial-mesenchymal transition (EMT), where downregulation of E-cadherin, a classical cadherin, enables cells to acquire migratory and invasive properties. This process is mediated by transcription factors such as Snail and Twist, which repress E-cadherin expression and promote mesenchymal markers like vimentin, thereby allowing tumor cells to break away from the primary site.^[66]^[67] Integrins contribute to promigratory roles in cancer through dynamic switching of subunits, enhancing tumor invasion into surrounding tissues. For instance, upregulation of αvβ3 integrin in various carcinomas facilitates attachment to extracellular matrix components like fibronectin and vitronectin, promoting matrix metalloproteinase activity and basement membrane degradation.^[68] This switch from epithelial-like integrins (e.g., α2β1) to pro-invasive ones like αvβ3 correlates with increased motility and is observed in melanoma and breast cancer progression.^[68] Members of the immunoglobulin superfamily (IgSF) CAMs, such as ICAM-1 and VCAM-1, mediate tumor-endothelium interactions that support extravasation during metastasis. These molecules on tumor cells bind endothelial ligands, stabilizing transient contacts and aiding diapedesis in metastatic niches.^[69] In the metastatic cascade, selectins enable initial tumor cell capture in circulation by mimicking leukocyte rolling on vascular endothelium. E-selectin and P-selectin on activated endothelial cells interact with sialylated ligands on tumor cells, facilitating shear-resistant rolling and subsequent firm adhesion in distant organs like the lung and liver.^[70]^[71] Neural cell adhesion molecule (NCAM), particularly its polysialylated form (polySia-NCAM), drives dissemination in neuroblastoma by reducing homophilic adhesion and enhancing migratory behavior, leading to micrometastases in bone marrow and soft tissues.^[72] Therapeutic strategies targeting CAMs in cancer have focused on disrupting these aberrant interactions. Monoclonal antibodies against ICAM-1 have shown preclinical efficacy in multiple myeloma by blocking tumor cell adhesion and enhancing immune-mediated cytotoxicity, with antibody-drug conjugates demonstrating potent antitumor activity in xenograft models.^[73] Integrin inhibitors like cilengitide, which targets αvβ3 and αvβ5, have been evaluated in clinical trials for glioblastoma and other solid tumors; however, phase III trials combining cilengitide with temozolomide and radiotherapy failed to improve overall survival, highlighting challenges in translating preclinical promise to clinical outcomes.^[74] More recently, as of 2025, novel antibody-drug conjugates targeting integrins, such as sigvotatug vedotin directed against integrin β6, have shown early efficacy in phase I/II trials for non-small cell lung cancer, offering promising new avenues for integrin-based therapies.^[75]

Roles in Inflammation and Immunity

Cell adhesion molecules (CAMs) play pivotal roles in orchestrating leukocyte recruitment during inflammation and immune responses through the multi-step process of extravasation. Selectins, including P-selectin, E-selectin, and L-selectin, mediate the initial tethering and rolling of leukocytes on activated endothelium by binding to sialyl-Lewis X carbohydrates, slowing down circulating immune cells in response to inflammatory signals like TNF-α and IL-1.^[76] This rolling phase positions leukocytes to sense chemokines presented on the endothelial surface, which trigger intracellular signaling for subsequent firm adhesion.^[76] Integrins then enable stable arrest following chemokine activation; for instance, the β2-integrin LFA-1 (αLβ2) on leukocytes binds to ICAM-1 on endothelium, converting transient interactions into firm adhesion under shear flow conditions.^[76] This step is crucial for immune cell activation and migration toward inflamed tissues. Immunoglobulin superfamily (IgSF) CAMs, such as ICAM-1 and PECAM-1, further support firm adhesion and facilitate diapedesis, where leukocytes transmigrate through endothelial junctions; PECAM-1 homophilic interactions guide leukocytes across the monolayer, ensuring efficient immune surveillance.^[76] These coordinated CAM functions underpin acute inflammatory responses, such as in infection or injury, by directing leukocytes to sites of need. In chronic inflammation, CAM dysregulation sustains leukocyte infiltration and tissue damage. VCAM-1, an IgSF member, is upregulated on endothelium at atherosclerosis-prone sites in hypercholesterolemic models like ApoE-deficient mice, driven by cholesterol exposure and cytokines, promoting focal monocyte recruitment and early lesion formation.^[77] This selective expression facilitates persistent vascular inflammation, contributing to plaque development. Cadherins, particularly E-cadherin in epithelial barriers and VE-cadherin in endothelium, maintain tissue integrity but are disrupted during chronic gut inflammation like colitis. In inflammatory bowel disease (IBD), TNF-α and IFN-γ induce E-cadherin redistribution and loss of junctional integrity, increasing paracellular permeability and allowing bacterial translocation that exacerbates mucosal inflammation.^[78] Similarly, IFN-γ promotes VE-cadherin internalization and degradation in vascular endothelium, heightening permeability and immune cell extravasation in IBD pathogenesis.^[79] CAM alterations also drive autoimmunity by impairing immune regulation. In multiple sclerosis (MS), polysialylated neural cell adhesion molecule (PSA-NCAM) is aberrantly re-expressed on demyelinated axons within plaques, potentially inhibiting oligodendrocyte process extension and remyelination, thus perpetuating neurodegeneration.^[80] Therapeutic strategies target these dysregulations; natalizumab, a monoclonal antibody, binds the α4 subunit of integrins (α4β1 and α4β7), non-competitively blocking their interaction with VCAM-1 and MAdCAM-1 to prevent lymphocyte trafficking across the blood-brain barrier, significantly reducing MS relapse rates.^[81] Resolution of inflammation involves CAM shedding to limit excessive immune responses. ADAM proteases, notably ADAM17, cleave ectodomains of CAMs like L-selectin from leukocytes and VCAM-1 from endothelium, reducing cell adhesion and promoting detachment to dampen recruitment and facilitate tissue repair.^[82] This regulated proteolysis ensures timely termination of inflammatory cascades, preventing chronicity.^[83]

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