Selectin Related Peptides

Definition
The selectins are three related receptors that initiate rolling of leukocytes on activated platelets or endothelium through Ca2+-dependent recognition of cell surface carbohydrates 1.

Related Peptides
The selectin family consists of three closely related cell-surface molecules with differential expression by leukocytes, [L-selectin (MEL-14, LAM-i, CD62L)], platelets, [P-selectin (PADGEM, GMP-140, CD62P)], and vascular endothelium [E-(ELAM-i, CD62E) and P-selectin] 2.

Discovery
Before 1989, L-, P-, and E-selectin were on different experimental pathways, although certain similarities can be seen in retrospect. All three selectins were identified using antibodies. L-selectin, the first of the selectins to be studied and was recognized as an adhesion molecule by using a monoclonal antibody (MEL-14) raised against a murine lymphoma. P-selectin (CD62) was discovered by investigators interested in the biochemical events associated with platelet activation. The discovery of E-selectin involved a monoclonal antibody-based strategy that combined identification of a cellular activation antigen and adhesion blocking 3.

Structural Characteristics
All of the selectins have a unique and characteristic extracellular region composed of an amino terminal calcium-dependent lectin domain, an epidermal growth factor (EGF)2 -like domain, and two to nine short consensus repeat (SCR) units homologous to domains found in complement binding proteins 2.

Mode of Action
Leukocyte rolling and adhesion to endothelium are dynamic processes that involve multiple adhesion receptors and the active participation of the cells involved. It is unlikely that the selectins merely mediate the passive “adsorption” of leukocytes to the endothehial surface, but rather the selectins are likely to direct these processes. Regulatory mechanisms that control these events include the rapid mobilization of presynthesized P-selectin to the cell surface, increased rates of selectin protein synthesis, induced transcription of the E-selectin gene, changes in cycling of E- and P-selectins from the cell surface to intracellular compartments, rapid shedding of L-selectin from the cell surface, activation-induced changes in L-selectin avidity for ligands, and alterations in cytoskeletal associations. Control of selectin ligand function through induction of their synthesis, differential glycosylation, and release from the cell surface are also important regulatory events. Further, coordinated selectin and integrin function is essential for leukocyte entry into tissues. Also important are a host of locally active inflammatory mediators and chemokines responsible for initiating and perpetuating the inflammatory process. The tetrasaccharide sialyl Lewisx (sLex, CD158) has been identified as a prototype ligand for both P- and E-selectin, although all three selectins can bind sLex and sialyl Lewisx under the appropriate conditions. L-selectin (CD62L) binds to a ligand tentatively designated as GIyCAM while E-selectin (CD62E) and P-selectin (CD62P) bind to ligands bearing sLex (CD158) -related determinants on the surface of the neutrophil. Rolling is hypothesized to allow the leukocytes to interact with locally released inflammatory mediators and chemokines such as IL-8. This initiates firm adhesion mediated through the integrins (CD11a and CD11b) binding to ICAM-1 (CD54) and other ligands followed by leukocyte diapedesis between endothelial cells, which is mediated in part by CD31 2.

Functions
The selectin family of adhesion molecules mediates the initial attachment of leukocytes to venular endothelial cells before their firm adhesion and diapedesis at sites of tissue injury and inflammation. In contrast to most other adhesion molecules, selectin function is restricted to leukocyte interactions with vascular endothelium. Multiple studies indicate that the selectins mediate neutrophil, monocyte, and lymphocyte rolling along the venular wall. The generation of selectin-deficient mice has confirmed these findings and provided further insight into how the overlapping functions of these receptors regulate inflammatory processes. Selectin-directed therapeutic agents are now proven to be effective in blocking many of the pathological effects resulting from leukocyte entry into sites of inflammation. Future studies are focused on how the selectins interact with the increasing array of other adhesion molecules and inflammatory mediators 2.

References
1. McEver RP (1994). Selectins. Curr Opin Immunol., 6(1):75-84.
2. Tedder TF, Steeber DA, Chen A, Engel P (1995). The selectins: vascular adhesion molecules. Faseb J, 9(10):866-873.
3. Bevilacqua MP, Nelson RM (1993). Selectins. J. Clin. Invest., 91(2)379-387.