Integrin
Introduction
Integrins are a family of cell surface receptors that facilitate cell-extracellular matrix (ECM) adhesion. They are integral membrane proteins composed of alpha and beta subunits, which form heterodimers. These receptors play crucial roles in various cellular processes, including cell signaling, migration, proliferation, and survival. Integrins are involved in the regulation of the cytoskeleton and the transmission of mechanical signals from the ECM to the cell interior, a process known as mechanotransduction.
Structure and Composition
Integrins are composed of two non-covalently associated subunits: an alpha (α) and a beta (β) subunit. Each subunit spans the cell membrane and has a large extracellular domain, a single transmembrane helix, and a short cytoplasmic tail. There are 18 different alpha subunits and 8 different beta subunits in humans, which can combine to form 24 distinct integrin heterodimers.
Alpha Subunits
The alpha subunits are characterized by a seven-bladed β-propeller domain at the N-terminus, followed by a thigh domain, two calf domains, and a transmembrane domain. Some alpha subunits contain an additional inserted (I) domain, which is involved in ligand binding.
Beta Subunits
The beta subunits contain a hybrid domain, a plexin-semaphorin-integrin (PSI) domain, four epidermal growth factor (EGF)-like repeats, a β-tail domain, and a transmembrane domain. The cytoplasmic tails of beta subunits are critical for interactions with intracellular proteins and signaling pathways.
Ligand Binding and Specificity
Integrins recognize and bind to a wide variety of ECM proteins, including fibronectin, collagen, laminin, and vitronectin. The specificity of ligand binding is determined by the combination of alpha and beta subunits. The ligand-binding site is located at the interface between the alpha and beta subunits and often involves the I domain in alpha subunits that possess it.
Activation and Conformational Changes
Integrins exist in different conformational states: inactive (bent), intermediate, and active (extended). Activation of integrins can be triggered by inside-out signaling, where intracellular signals induce conformational changes that increase the affinity of integrins for their ligands. Conversely, outside-in signaling occurs when ligand binding induces conformational changes that propagate intracellularly, leading to various cellular responses.
Signal Transduction
Integrins are key players in signal transduction pathways. Upon ligand binding, integrins cluster and recruit various intracellular signaling molecules, including focal adhesion kinase (FAK), Src family kinases, and integrin-linked kinase (ILK). These molecules initiate downstream signaling cascades that regulate cell survival, proliferation, and migration.
Focal Adhesions
Focal adhesions are dynamic multi-protein complexes that form at sites where integrins bind to the ECM. They serve as signaling hubs and structural links between the ECM and the actin cytoskeleton. Key components of focal adhesions include talin, vinculin, paxillin, and zyxin.
Role in Cellular Processes
Integrins are involved in numerous cellular processes:
Cell Migration
Integrins mediate cell migration by coordinating the formation and disassembly of focal adhesions. This process is essential for wound healing, immune responses, and embryonic development.
Cell Proliferation and Survival
Integrin signaling can promote cell proliferation and survival through the activation of pathways such as the PI3K/Akt and MAPK/ERK pathways. These pathways are critical for cell growth and protection against apoptosis.
Mechanotransduction
Integrins play a central role in mechanotransduction, the process by which cells sense and respond to mechanical forces. Integrin-mediated adhesion to the ECM allows cells to detect changes in the mechanical properties of their environment and adjust their behavior accordingly.
Integrins in Disease
Dysregulation of integrin function is implicated in various diseases, including cancer, fibrosis, and inflammatory conditions. In cancer, integrins can promote tumor growth, angiogenesis, and metastasis. In fibrosis, aberrant integrin signaling can lead to excessive ECM deposition and tissue scarring. In inflammatory diseases, integrins are involved in the recruitment and activation of immune cells.
Therapeutic Targeting of Integrins
Given their involvement in numerous pathological processes, integrins are attractive targets for therapeutic intervention. Several integrin inhibitors have been developed and are in clinical use or undergoing clinical trials. These include monoclonal antibodies, small molecule inhibitors, and peptide mimetics.