- Integrins are a large family of type I transmembrane heterodimeric glycoprotein receptors that play central roles in mediating both cell–extracellular matrix (ECM) and cell–cell interactions.
- Alongside cadherins, selectins, and members of the immunoglobulin superfamily (IgSF), integrins represent one of the four major classes of cell adhesion molecules (CAMs).
- These molecules are crucial in maintaining tissue integrity and architecture and are highly conserved across the metazoan kingdom, with homologs present in organisms as diverse as sponges, corals, nematodes, echinoderms, and mammals.
- Structurally, integrins are composed of two non-covalently associated subunits: an α (alpha) and a β (beta) chain, both of which are single-pass type I transmembrane proteins.
- Each integrin heterodimer includes a large extracellular domain that interacts with ligands in the extracellular space, a single membrane-spanning region, and a typically short cytoplasmic tail that connects to intracellular signaling and structural components.
- To date, 18 α and 8 β subunits have been identified in mammals, which combine in a specific manner to form at least 24 distinct integrins.
- Each αβ heterodimer exhibits selective binding to different ECM components such as fibronectin, collagen, and laminin, thereby determining the integrin’s functional specificity.
- Despite lacking intrinsic catalytic activity, integrins are key signaling hubs. In their inactive state, integrins adopt a bent conformation with low ligand affinity. Upon activation, they extend into an open conformation that allows high-affinity ligand binding. This activation can be triggered by two distinct but interconnected mechanisms: outside-in and inside-out signaling. Outside-in signaling occurs when integrins bind ligands from the extracellular environment, initiating intracellular responses that influence cytoskeletal organization, gene expression, and cellular behavior. Inside-out signaling is initiated by intracellular activators—such as talin and kindlin—that bind to the cytoplasmic tails of β subunits, inducing conformational changes that increase ligand-binding affinity.
- Integrin-mediated signaling intersects with many other pathways, including receptor tyrosine kinase (RTK) pathways. For instance, integrins often cooperate with growth factor receptors such as EGFR or VEGFR to modulate cellular responses to environmental cues. Activated integrins engage with focal adhesion kinase (FAK), Src-family kinases, PI3K, and small Rho GTPases like RhoA, Rac1, and Cdc42. These interactions regulate essential cellular processes including migration, proliferation, survival, and differentiation. Furthermore, integrins serve as mechanosensors that transmit physical cues from the ECM to the cytoskeleton, influencing cell behavior through mechanotransduction.
- The biological roles of integrins are vast and critical. During embryonic development, integrins guide tissue patterning, organ formation, and stem cell differentiation. In adults, they contribute to tissue maintenance and repair, immune cell trafficking, and angiogenesis. Importantly, integrins also maintain homeostasis by mediating stable interactions with the ECM and neighboring cells. However, when integrin function is dysregulated, the consequences can be pathologic. Aberrant integrin expression or signaling has been implicated in autoimmune diseases, thrombosis, and various forms of cancer.
- In oncology, integrins such as αvβ3, α6β4, and α5β1 are frequently upregulated in tumor cells and are associated with enhanced invasion, metastasis, angiogenesis, and therapy resistance. In inflammatory and autoimmune disorders like multiple sclerosis and Crohn’s disease, inappropriate activation of integrins such as α4β1 (VLA-4) and αLβ2 (LFA-1) promotes excessive immune cell adhesion and infiltration. Additionally, in thrombosis, platelet-specific integrins like αIIbβ3 mediate platelet aggregation, making them prime targets for anti-platelet therapies.
- In conclusion, integrins function as dynamic, versatile adhesion and signaling receptors that bridge the extracellular environment with intracellular networks. Their role in regulating cellular mechanics and communication is indispensable to normal physiology and tissue integrity. At the same time, their misregulation contributes to the pathogenesis of numerous diseases. Ongoing research into integrin biology continues to reveal therapeutic opportunities across a wide spectrum of clinical conditions.
