LSelectin CD62L

L-Selectin (previously referred to as LECAM-1, LAM-1, Mel-14 antigen or Leu8 antigen) is expressed constitutively on leukocytes. It was

Leu kocyte

Leu kocyte

Figure 2 Selectins and their glycoprotein ligands. The lectin domains of the selectins (LEC) bind to clustered carbohydrate epitopes present on the protein backbone of sialomucins. L-Sel-ectin recognizes at least three distinct sialomucins, GlyCAM-1, CD34 expressed on high endothelial venules of peripheral lymph nodes and also MAdCAM-1 expressed on high endothelial venules of mesenteric lymph nodes and Peyer's patches. Two endothelial selectins, E- and P-selectin recognize ESL-1 and PSGL-1, respectively, both of which are expressed on neutrophils. With GlyCAM-1, CD34, MAdCAM-1 and PSGL-1, O-linked sugars are recognized by selectins, whereas with ESL-1, W-linked sugars are recognized by E-selectin.

Figure 2 Selectins and their glycoprotein ligands. The lectin domains of the selectins (LEC) bind to clustered carbohydrate epitopes present on the protein backbone of sialomucins. L-Sel-ectin recognizes at least three distinct sialomucins, GlyCAM-1, CD34 expressed on high endothelial venules of peripheral lymph nodes and also MAdCAM-1 expressed on high endothelial venules of mesenteric lymph nodes and Peyer's patches. Two endothelial selectins, E- and P-selectin recognize ESL-1 and PSGL-1, respectively, both of which are expressed on neutrophils. With GlyCAM-1, CD34, MAdCAM-1 and PSGL-1, O-linked sugars are recognized by selectins, whereas with ESL-1, W-linked sugars are recognized by E-selectin.

initially characterized by monoclonal antibody (mAb) Mel-14 as the murine homing receptor mediating lymphocyte binding to HEVs in peripheral lymph nodes. However, recent studies indicate that L-selectin is expressed on nonlymphoid leukocytes and is involved in the leukocyte traffic to inflamed tissues.

cDNA encoding L-selectin has been cloned in mice, humans, rats and cattle. L-Selectin has a characteristic lectin domain, an EGF domain, and two consensus repeats of the complement-regulatory protein domains. Human L-selectin has a core protein of 37 kDa with seven potential N-glycosylation sites, but no O-linked glycan appears to be present. Post-translational glycosylation yields L-selectin of different molecular sizes that are differentially expressed in various leukocyte subsets; 75 kDa in lymphocytes, 95-105 kDa in neutrophils and 110 kDa in monocytes. The L-selectin gene is located on human chromosome 1 and on murine chromosome 1 in close association with E- and P-selectin genes in both species. The proximity of these genes and similarity in the sequence of selectin genes (40-60% at the nucleotide level) suggest that they originated from a common primordial ancestor.

A unique feature of L-selectin is that it is rapidly shed from the cell surface upon activation. It is cleaved at the membrane-proximal site as a result of proteolysis, and increased levels of soluble L-selectin are present in the plasma of patients with sepsis, leukemia and the acquired immune deficiency syndrome (AIDS). Although the biochemical nature of this proteolytic enzyme, 'secretase' or 'sheddase', remains to be fully elucidated, a novel type of zinc-dependent metalloprotease, similar to the one involved in the processing of membrane-bound tumor necrosis factor ct (TNFa), appears to play a key role in proteolysis. Inhibition of the activity of this enzyme leads to reduced neutrophil rolling velocity under hydro-dynamic flow conditions, resulting in increased accumulation of neutrophils. This suggests that the shedding process of L-selectin occurs very rapidly during rolling interactions and may be necessary for subsequent leukocyte adhesion and transmigration.

L-Selectin recognizes sialylated Lewis" and sialyl-ated Lewis" (sLea; Neu5Aca2-3Gal(31-3(Fucal-4)GlcNAc), as do other selectins. Similar to P-sel-ectin, L-selectin also binds to sulfatides and sulfated polysaccharides such as fucoidan and heparin. A group of O-glycosylated mucins decorated with sialic acid, termed sialomucins, represents the protein ligands for L-selectin. They are GlyCAM-1, CD34 and MAdCAM-1. GlyCAM-1, which bears sLex-type carbohydrates, is a secretory molecule expressed specifically on HEVs of peripheral lymph nodes and probably acts as a regulator for L-selectin-mediated cell adhesion. CD34 is a transmembrane glycoprotein expressed extensively on blood vessels and hematopoietic stem cells, neither of which bind L-selectin under normal circumstances. Appropriate glycosylation appears to confer the ability to bind to L-selectin, and a specifically glycosylated form of CD34 expressed on HEVs serves as a ligand for L-selectin. However, mice deficient of CD34 by gene targeting possess almost normal lymph node architecture, and hence, CD34 is apparently not the sole ligand responsible for L-selectin-mediated lymphocyte trafficking into peripheral lymph nodes. MAdCAM-1 is expressed on HEVs of Peyer's patches and venules in intestinal lamina propria, and has been shown to bind L-selectin and a4(37-integrin. Recognition of vascular MAdCAM-1 by lymphocyte «4f3— integrin plays a crucial role in lymphocyte trafficking into intestinal lymphoid tissues. The physiological significance of L-selectin binding to MAdCAM-1 is unclear at present.

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