Mechanisms contributing to the activity of integrins on leukocytes

Abstract

Understanding how the integrins on leukocytes operate is important because these receptors control the activity of leukocytes in all phases of their lives. Thus integrins control leukocyte development and maturation in bone marrow, the circulation of naive cells in secondary lymphoid tissue, e.g. the lymph nodes, and leukocyte responses to inflammatory signals emanating from injured tissues. Using as an example LFA-1, which is expressed by all leukocytes, we outline how the activity of this integrin is modified to meet the challenges posed by these leukocyte activities. Briefly, we discuss three means by which LFA-1 is adapted to bind more efficiently to its chief ligand, ICAM-1. LFA-1 can undergo changes in conformation leading to increased affinity, can be clustered on the membrane and, finally, when activated can move into the lipid raft compartment of the membrane. The study of humans with the beta2 deficiency syndrome termed leukocyte adhesion deficiency (LAD)-1 and analysis of LFA-1 null mice has given further insight into integrin activation mechanisms and the in vivo roles of LFA-1 and other leukocyte integrins.

Insulin-like Growth Factor-independent Effects Mediated by a C-terminal Metal-binding Domain of Insulin-like Growth Factor Binding Protein-3

“…The direct involvement of ␣ and ␤ integrins, and a requirement for phosphatidylinositol 3-kinase, is also indicated in this work. In this regard it is interesting to note that localization of integrins to lipid rafts can modulate signal transduction in some cell types (48,49) and that caveolae profoundly influence cytoskeletal organization (50). Glycosphingolipids are internalized from the plasma membrane of human skin fibroblasts by clathrin-independent caveolar endocytosis and are rapidly delivered to early endosomes by a RAB5a-independent mechanism, where they colocalize with transferrin.…”

Integrins as a distinct subtype of dependence receptors

“…These cells are often metabolically quiescent, and tend to regulate their integrins to exist in a low affinity state, as shown by protein conformation and ligand-binding investigations. [82][83][84][85] These conformational changes exist in the extracellular ligand-binding domains and the cytoplasmic domain, 86 which may influence the capacity to influence apoptosis and cell survival. However, the expression of hematopoietic cellspecific proteins, as well as the quiescent metabolism of these cells, likely also contributes to cell survival in the absence of a substrate ligand.…”

Characterization of Mannheimia (Pasteurella) haemolytica leukotoxin interaction with bovine alveolar macrophage β2 integrins

“…They are: CD11a/CD18, also known as LFA-1 (lymphocyte function associated antigen-1); CD11b/CD18, also known as Mac-1 or CR3; CD11c/CD18, also known as P150/ 95 or CR4; and CD11d/CD18. The human LFA-1 subunits (CD11a and CD18) are products of separate genes [15,18,41,47] and are expressed as heterodimers on the surface of all leukocytes. Each subunit is composed of a large extracellular domain (~1000 residues for the α-subunit and ~ 750 residues for the β-subunit), a single transmembrane domain of ~20 amino acids and a short cytoplasmic domain of ~50 amino acids.…”