Cells in multicellular organisms do not exist in isolation but are embedded in a complex network of adhesive contacts and extracellular macromolecules that together determine tissue architecture, mechanical properties, and signaling dynamics. Cell adhesion molecules and the extracellular matrix (ECM) coordinate development, maintain tissue integrity, and are central to wound healing, immune responses, and cancer metastasis.
Cell-Cell Adhesion Junctions
Epithelial and endothelial cells form specialized intercellular junctions that provide mechanical strength and barrier function. Adherens junctions are based on cadherin adhesion molecules that form homophilic interactions between adjacent cells; the cytoplasmic domain of cadherins binds β-catenin, which links to α-catenin and the actin cytoskeleton, creating a continuous adhesion belt around the cell. Tight junctions, composed of claudins and occludins, seal the paracellular space and establish apical-basal polarity by preventing lateral diffusion of membrane proteins. Desmosomes use desmocollin and desmoglein cadherins that link to intermediate filaments through plakin family proteins, providing mechanical resilience in tissues subjected to shear stress such as skin and heart muscle. Gap junctions, formed by connexin proteins assembled into hexameric connexons, create direct channels for small molecules and ions between adjacent cells, enabling electrical and metabolic coupling essential for coordinated tissue functions such as cardiac contraction and neuronal signaling.
Cadherins and Selectins
Cadherins are calcium-dependent adhesion molecules that mediate homophilic cell-cell adhesion. Classical cadherins, including E-cadherin (epithelial), N-cadherin (neural), and VE-cadherin (vascular endothelial), are single-pass transmembrane proteins with extracellular cadherin repeats that form adhesive dimers with identical cadherins on opposing cells. Cadherin expression patterns determine tissue segregation during development: cells expressing different cadherins sort into separate layers, a phenomenon essential for gastrulation and organogenesis. Selectins are calcium-dependent lectins that mediate transient adhesion of leukocytes to vascular endothelium during inflammation. L-selectin on leukocytes, E-selectin on activated endothelium, and P-selectin on platelets and endothelium bind glycosylated ligands such as PSGL-1, mediating the rolling of leukocytes along the vessel wall before firm adhesion and extravasation.
Integrins
Integrins are heterodimeric transmembrane receptors composed of α and β subunits that mediate cell-ECM adhesion and bidirectional signaling. Eighteen α subunits and eight β subunits assemble into 24 distinct integrin heterodimers with specific ligand-binding preferences, including collagen receptors (α1β1, α2β1), laminin receptors (α3β1, α6β1, α7β1), and RGD (arginine-glycine-aspartate) motif-binding receptors (αVβ3, α5β1) that recognize fibronectin, vitronectin, and fibrinogen. Integrins exist in a bent, inactive conformation and undergo conformational activation through inside-out signaling triggered by intracellular signals such as talin and kindlin binding to the cytoplasmic β tail, switching to an extended, high-affinity state. Clustering of activated integrins at focal adhesions links the ECM to the actin cytoskeleton through adapter proteins including talin, vinculin, paxillin, and focal adhesion kinase (FAK), which assemble into dynamic signaling platforms that regulate cell proliferation, survival, migration, and differentiation.
Extracellular Matrix Components
The ECM is a complex network of secreted macromolecules organized into a scaffold that provides structural support and biochemical signals. Collagens are the most abundant ECM proteins, with at least 28 types in vertebrates; fibrillar collagens (types I, II, III, V) assemble into strong triple-helical fibers that provide tensile strength, while network-forming collagens (type IV) form sheet-like networks in basement membranes. Elastin, together with microfibrillar glycoproteins including fibrillins, forms elastic fibers that allow tissues such as skin, lungs, and arteries to stretch and recoil. Proteoglycans consist of a core protein with covalently attached glycosaminoglycan (GAG) chains, including hyaluronan, chondroitin sulfate, heparan sulfate, and keratan sulfate, that sequester water and growth factors, providing hydration and regulating signaling molecule availability. Multi-adhesive matrix glycoproteins including fibronectin, laminins, tenascin, and thrombospondin contain multiple domains that bind cells, other ECM components, and growth factors, organizing the ECM architecture and modulating cell behavior.
Basement Membranes
Basement membranes are specialized sheet-like ECM structures that underlie epithelial and endothelial cells and surround muscle, nerve, and fat cells. The main components are type IV collagen, laminins, nidogen, and the heparan sulfate proteoglycan perlecan. Laminins form cross-shaped structures that self-assemble into networks and bind to integrins and dystroglycan on cell surfaces. Nidogen bridges laminin and collagen IV networks, stabilizing the basement membrane architecture. Type IV collagen networks provide mechanical stability, and perlecan contributes to charge-selective filtration in the glomerular basement membrane of the kidney. Basement membranes serve as selective permeability barriers, provide anchorage for cell polarity, and present immobilized growth factors and chemokines that guide cell migration during development and immune surveillance.
ECM Degradation and Remodeling
The ECM undergoes continuous remodeling through the regulated action of matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases that collectively degrade all ECM components. MMPs are secreted as inactive zymogens and activated by proteolytic cleavage, and their activity is tightly controlled by tissue inhibitors of metalloproteinases (TIMPs). ECM degradation is essential for developmental morphogenesis, angiogenesis, and tissue repair, but excessive MMP activity contributes to pathological matrix destruction in arthritis, atherosclerosis, and tumor invasion. During cancer metastasis, tumor cells upregulate MMP expression to degrade basement membranes and invade surrounding tissue, enter blood or lymphatic vessels, and establish secondary tumors at distant sites.
Cell Migration
Cell migration is a coordinated, multi-step process driven by dynamic reorganization of the actin cytoskeleton and integrin-mediated adhesion. Migration begins with protrusion of the leading edge through actin polymerization, forming sheet-like lamellipodia or finger-like filopodia that explore the ECM environment. New adhesions form at the leading edge between integrins and ECM components, providing traction points. The cell body moves forward through actomyosin contraction, and adhesions at the rear of the cell disassemble, allowing retraction of the trailing edge. Directional migration is guided by chemotactic gradients, haptotactic (adhesive) gradients, and contact guidance by ECM fiber alignment, with Rho family GTPases (Rho, Rac, Cdc42) acting as master regulators of cytoskeletal dynamics and adhesion turnover.
