integrine

Integrins are a family of cell surface receptors that mediate adhesion between cells and the extracellular matrix or between neighboring cells. They are heterodimers composed of one alpha and one beta subunit, and in humans 18 alpha and 8 beta subunits combine to form at least 24 distinct integrins. The large extracellular domains bind ligands such as fibronectin, laminin, collagen, and vitronectin, while the single-pass transmembrane domain connects to the cytoskeleton through short cytoplasmic tails.

Integrins function in bidirectional signaling. Inside-out activation, driven by intracellular signals that recruit proteins like talin and kindlin to the cytoplasmic tails, increases affinity for ligands. Outside-in signaling occurs when ligand binding induces conformational changes that trigger cytoskeletal rearrangements and activate signaling pathways, influencing cell adhesion, migration, proliferation, survival, and differentiation. This signaling integrates with pathways such as focal adhesion kinase (FAK), Src, PI3K, and MAPK.

Different integrin heterodimers mediate distinct adhesion events. For example, α5β1 and αvβ3 bind fibronectin and vitronectin, respectively, and αLβ2 (LFA-1) and αMβ2 (Mac-1) mediate leukocyte adhesion, while α4β1 (VLA-4) binds VCAM-1. Platelets use αIIbβ3 to regulate aggregation. In many tissues, integrins link the ECM to the actin cytoskeleton through adaptor proteins, contributing to processes such as angiogenesis and tissue integrity.

Clinical relevance includes roles in thrombosis, cancer metastasis, and inflammatory diseases. Therapeutic strategies target integrins with monoclonal antibodies or small molecules to block specific subtypes, exemplified by anti-platelet drugs targeting αIIbβ3, and anti-lymphocyte or anti-adhesion therapies such as natalizumab and vedolizumab. These therapies can carry risks, including infections and, in some cases, progressive multifocal leukoencephalopathy.