Integrin Activation and Signal Transduction

Dear Colleagues,

Integrins are heterodimeric αβ cell surface adhesion molecules. At rest, integrins do not bind ligands on other cells or in the extracellular matrix (ECM). Integrins are activated by inside–out signaling, which causes major rearrangements in the conformation of the extracellular domain. Inside-out signaling can be triggered by G-protein-coupled receptors (GPCRs), growth factor receptors, cytokine receptors, and other signaling molecules. Once integrins bind their ligands, they become transducers of outside–in signaling, providing key signals for cell adhesion, growth, survival, and other functions.

Many of the 24 human (and mouse) integrins are involved in anchoring epithelial, endothelial, and mesenchymal cells to the ECM. Such cells show no or minor motility and are always attached; hence, these integrins are always somewhat activated. Integrins on blood cells show the most dramatic activation response, with their affinity for ligand increasing 10,000-fold. Such integrins are found on platelets and leukocytes. When these integrins are activated, they cause blood cells to arrest and adhere to the vessel wall.

Integrin activation requires talin-1, at least one of the kindlins (kidlin-2 or kindlin-3), and Rap1. In some cells, the adapter molecule RIAM is also required. This Special Issue will touch on the intracellular mechanisms underlying integrin activation.

Some integrins contain von Willebrand A domain (also called inserted or I domain). In such integrins, the ligand binding site is situated in the α I domain, which binds the β I-like domain via an internal ligand. In some integrins, the conformational change in the I domain or I-like domain can be detected by conformation-specific monoclonal antibodies (mAbs). Integrins without an I domain bind ligand at the interface between the N-terminal domains of the α and β subunits. Some mAbs can detect the activated conformation of integrins without an I domain. Integrin activation can also be measured by mAbs to the ligand binding site (so-called LIBS antibodies), or by the soluble oligomeric ligand itself.

Activated integrins not only change the affinity of the ligand binding site, but also extend from a bent conformation at rest. This extension, or standing up, exposes epitopes hidden in the bent knee of resting integrins.

Defects in integrins and integrin activation cause various inherited diseases. One of the most common is Glanzmann thrombasthenia, caused by mutations in ITGA2B or ITGA3. These mutations affect platelets and cause bleeding. Mutations in ITGB2 cause leukocyte adhesion deficiency type 1 (LAD-I), characterized by severe recurrent infections in mucosal tissues and skin. Mutations in kindlin-3 cause LAD-III, a severe combined disorder of both leukocyte and platelet integrin activation leading to infections and bleeding.

The purpose of this Special Issue is to bring together leading scientists in the field and provide a broad overview of the mechanisms, functions, and consequences of integrin activation. We look forward to your contributions.

Prof. Dr. Klaus Ley
Guest Editor

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• integrin
• talin
• kindlin
• Rap-1
• conformation
• ligand binding
• cell surface receptor
• integrin-deficiency diseases