Selectins

Selectins are a family of membrane glycoproteins that are divalent cation-dependent and bind to specific carbohydrates containing sialylated moieties. They are composed of leukocyte (L)-selectins, endothelial (E)-selectins and platelet (P)-selectins. L-selectins are expressed on most leukocytes, whereas vascular endothelial cells express E-selectins and P-selectins. Initial binding of leukocytes with vascular endothelium involves selectins and consequently they play an important role in leukocyte trafficking. 

Mammalian Sialic Acid-Binding Proteins (for Selectins See Table VII) 

Blood (factor H of alternative complement pathway) Murine macrophages (sialoadhesin) 

Bovine heart (calcyclin) Human placenta (sarcolectin) B lymphocytes (CD22) 

Zeng and Gabius (1991) Zeng and Gabius (1992a) Sgroi et al. (1993), 

All three members of this family (Bevilacqua et al., 1991) show a similar primary structure (Bevilacqua et al., 1989 Johnston et al., 1989 Lasky et al., 1989 Larsen et al., 1989 Siegelman et al., 1989 reviewed in Lasky, 1992  

There are three groups of adhesion molecules responsible for these processes the selectins, the integrins and the immunoglobulin (Ig) superfamily. 

There are three types of selectins responsible for the attachment of leukocytes to the endothelium, as shown in Table 3.1. Selectins possess three types of domains a C-type lectin domain, an epidermal growth-factor-like domain and between two and nine regulatory domains. 

On the neutrophil, the major selectin expressed is L-selectin. This molecule is constitutively expressed on mature neutrophils but may be expressed at low levels (50% of adult) in neonates. Stimulation of endothelial cells with thrombin, histamine, IL-1 and some other agents induces neutrophils (and other leukocytes) to leave the circulation and adhere to the endothelium. They do this by rolling onto the surface of the endothelium, to which they attach via P-selectin translocated from storage sites in Weibel-Palade bodies to the surface of the endothelium upon activation. The expression of P-selectin is short-lived and is replaced on the endothelial surface by E-selectin (whose expression is also regulated by some cytokines), which continues the endothelial-leukocyte interaction. 

Rolling involves sequential attachment and detachment of the leukocyte with the endothelium. The selectin receptors bind very quickly and tether via recognition of their carbohydrate moieties with the ends of flexible pro- 

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Cell Adhesion. The membranes of leukocytes and platelets contain a variety of components that promote ceU-surface contact. Although numerous ceU-surface molecules are likely to play a role in ceU-surface adhesion, the group of selectins are of particular interest to research on this subject. Selectins are molecules that are known to promote leukocyte—platelet adhesion. However, selectin-based models have not been able to account for the fact that platelets are allowed to pass through the filter and leukocytes are not. 

These interactions involve adhesion proteins called selectins, which are found both on the rolling leukocytes and on the endothelial cells of the vascular walls. Selectins have a characteristic domain structure, consisting of an N-terminal extracellular lectin domain, a single epidermal growth factor (EGR) domain, a series of two to nine short consensus repeat (SCR) domains, a single transmembrane segment, and a short cytoplasmic domain. Lectin domains, first characterized in plants, bind carbohydrates... 

A diagram showing the interactions of selectins with their receptors. The selectin family of adhesion proteins. 

Lasky, L. A., 1995. Selectin-carbohydrate interactions and the initiation of die inflammatory response. Annual Review of Biochemistry 64 113-139. 

P-selectin, VEGFR2, VCAM, pPAR, CD55, Eotaxin-3, MCP-1... 

Frequently, the EAR is followed by a late phase response 4-6 h later and it is caused by the pulmonary sequestration of eosinophils, neutrophils, mast cells, and T-lymphocytes. This leukocyte recruitment depends on mast cell-derived mediators such as TNFa and various chemokines, as well as on the expression of adhesion molecules on leukocytes (e.g. VLA-4, CD11/18) and vascular endothelial cells (e.g. VCAM-1, ICAM-1, E-selectin). Products of these leukocytes have several functions First, they cause the second phase of bron-choconstriction, mucus secretion, and airway swelling second, they cause tissue destruction third, they launch and entertain the chronic inflammation. 

Integrins, selectins, cadherins, claudins and other cell adhesion molecules are involved in the interaction of cells with other cells or with extracellular matrix components. Some of them also serve as receptors by inducing outside-in or additional inside-out signaling. 

CD163 (Scavenger receptor) Adhesion molecules (ICAM-1, E-selectin)... 

In the very early phases of the acute inflammatory response most of the cells invading the damaged area are polymorphonuclear neutrophils, also denoted as PMNs, which serve as initial line of defense and source of proinflammatory cytokines. These cells, which usually live for 4-5 days, circulate in the blood until they are attracted by chemokines into injured tissues. Whereas physical injury does not recruit many neutrophils, infections with bacteria or fungi elicit a striking neutrophil response. The characteristic pus of a bacterial abscess is composed mainly of apoptotic (apoptosis) and necrotic PMNs. Emigration of neutrophils from the blood starts with a process denoted as margination where neutrophils come to lie at the periphery of flowing blood cells and adhere to endothelial cells (Fig. 1). L-Selectin is expressed... 

Inflammation. Figure 1 Sequence of events in the recruitment of leukocytes in postcapillary venules adjacent to injured tissue. At the site of lesion, diverse reactive substances stimulate the endothelium to produce inflammatory cytokines, chemoattractants and other inflammatory mediators. The cytokine-activated endothelium expresses adhesion molecules that lead to the low affinity interactions between leukocytes and endothelium, which is mediated by selectins and described as rolling. Subsequently integrins mediate the firm adhesion of leukocytes, which allows emigration of the cells from venules into the interstitial compartment. Activated mast cells, PMNs and macrophages secrete cytokines (TNFa), lipid mediators (LTB4) and other inflammatory players (histamine, NO). 

The three selectins are related both structurally and functionally. They are transmembrane proteins, with an N-terminal C-type actin domain, followed by an EGF repeat and a variable number of complement control protein (CCP) domains. Selectins bind carbohydrates, which are present in various glycoproteins. 

Figure 2. (1) Neutrophils circulating passively in blood capillary. (2) Chemoattractants may be detected by the circulating neutrophils, by the endothelial cells lining the lumen, or both in order that the neutrophils become adhesive. This adhesion is mediated by selectins, a group of cell surface proteins. Neutrophils roll on the surface of the endothelial cells and then actively locomote seeking out spaces between the endothelial cells. (3) The adhesive neutrophils begin to squeeze between endothelial cells. (4) Cells move through the extracellular matrix towards the site of infection. Here adhesion is low and may not be necessary for locomotion. (5) At the site of infection, neutrophils become trapped by increased adhesion where they phagocytose bacteria and liberate the contents of their granules. After Lackie (1982,1986).

Flgure10.23 Sialyl Lewis -related selectin inhibitorandfluorogenicscreening compound for transketolase prepared using enzymatic aldolization, and multienzymatic oxidation-aldolization strategy for the synthesis of bicyclic higher carbon sugars. 

Interact with specific carbohydrates Lectins, selectins (cell adhesion lectins), antibodies... 

C-type lectins Characterized by a Ca +-dependent carbohydrate recognition domain (CRD) includes the mammalian asialoglycoprotein receptor, the selectins, and the mannosebinding protein... 

Selectins Play Key Roles in Inflammation in Lymphocyte Homing... 

Selectins L-selectin PMN, lymphs CD34,Gly-CAM-L Sialyl-Lewis" and others... 

These are ligands for lymphocyte L-selectin the ligands for neutrophil L-selectin have not been identified. 

Figure 47-10. Schematic diagram of the structure of human L-selectin. The extracellular portion contains an amino terminal domain homologous to C-type lectins and an adjacent epidermal growth factor-like domain. These are followed by a variable number of complement regulatory-like modules (numbered circles) and a transmembrane sequence (blackdiamond). A short cytoplasmic sequence (open rectangle) is at the carboxyl terminal. The structures of P- and E-selectin are similar to that shown except that they contain more complement-regulatory modules.The numbers of amino acids in L-, P-, and E- selectins, as deduced from the cDNA sequences, are 385,789, and 589, respectively. (Reproduced, with permission, from Bevilacqua MP, Nelson RM Selectins. J Clin Invest 1993 91 370.)...

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