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Selectin Interactions
Published by Anonymous on 2007/9/27 (1533 reads)
1: Methods Mol Biol. 2006;347:343-58.


Quantitative measurement of selectin-ligand interactions: assays to identify a sweet pill in a library of carbohydrates.

Beauharnois ME, Neelamegham S, Matta KL.

Chemical and Biological Engineering, State University of New York at Buffalo, Buffalo, NY, USA.

Soluble oligosaccharides and glycoproteins can inhibit leukocyte adhesion during a range of vascular ailments including inflammation, thrombosis, and cancer metastasis. The design of such molecules in many cases is based on the structure of naturally occurring selectin ligands. In this case, synthetic selectin-ligand mimetics act as competitive inhibitors of cell adhesion. In an alternate approach, cell-permeable, small-molecule oligosaccharides have been shown to alter the metabolic pathways that lead to the biosynthesis of functional selectin-ligands. The addition of such molecules results in glycoproteins that are defective in their ability to bind selectins. Quantitative in vitro testing of the efficacy of the above inhibition strategies ideally requires the application of assays that mimic the in vivo physiological milieu in terms of the valency of selectin and selectin-ligands, the physiological fluid-flow conditions, and the use of blood cells. Assays that are performed in small volumes are preferable when the quantity of available inhibitor is scarce. Finally, the measurements must account for the rapid on- and off-rates of selectin-mediated binding interactions. This chapter addresses these issues by presenting methods to measure selectin function in enzyme-linked immunosorbent assay and flow cytometry-based static assays, cell-adhesion assays performed under shear flow in cone-plate viscometers, and Biacore surface plasmon resonance measurements of molecular-binding kinetics. Examples are presented where such methods are applied to measure the ability of simple oligosaccharides based on sialyl Lewis-X and complex molecules with the core-2 structure to block selectin function. Such methods may be extended to identify potent selectin antagonists in a library of carbohydrates.

Publication Types:
Research Support, N.I.H., Extramural
Review

PMID: 17072022 [PubMed - indexed for MEDLINE]

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2: Cancer Treat Res. 2006;130:125-40.


Tumor-microenvironment interactions: the selectin-selectin ligand axis in tumor-endothelium cross talk.

Witz IP.

Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel. ipwitz@post.tau.ac.il

Interactions of cancer cells with components of their microenvironment are crucial determinants in the decision making process which determines whether the cancer cells will progress towards a highly malignant phenotype or whether they will stay dormant or disappear altogether. The tumor microenvironment is composed of a plethora of soluble and cellular components. Many of these components deliver signals to tumor cells and thus modulate their phenotype thereby driving tumor progression. This chapter focuses on the interaction of tumor cells with endothelial cells through endothelial selectins and their fucosylated ligands expressed by the tumor cells. Comparisons are drawn between the utilization of this interaction axis by inflammatory leukocytes and by tumor cells.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 16610706 [PubMed - indexed for MEDLINE]

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3: Semin Thromb Hemost. 2002 Feb;28(1):53-66.


Heparin inhibition of selectin-mediated interactions during the hematogenous phase of carcinoma metastasis: rationale for clinical studies in humans.

Varki NM, Varki A.

Department of Medicine, Cancer Center, University of California, San Diego, La Jolla, California 92093-0687, USA. nvarki@ucsd.edu

Classic studies indicate that the formation of tumor cell-platelet complexes in the blood stream is important in facilitating the metastatic process. Metastasis in animal models can be inhibited by heparin, and retrospective analyses of heparin use in human cancer have shown promise. However, most follow-up human studies using vitamin K antagonists have failed, and conclusive proof for other previously proposed mechanisms of heparin action is lacking. Carcinoma progression and metastasis are associated with overexpression of sialylated fucosylated mucins. Structurally similar molecules happen to be natural ligands for vascular adhesion molecules called the selectins. Heparin also happens to be a good inhibitor of P-selectin, which is expressed on activated platelets or endothelial cells. We have found that heparin blocks P-selectin-mediated interactions of endogenous platelets with sialylated fucosylated mucins on circulating carcinoma cells and that this reduces tumor cell survival. The use of more specific and selective P-selectin inhibitors will some day help to dissect the relative importance of this mechanism of heparin action in cancer. Meanwhile, we suggest that the failure of vitamin K antagonists to improve cancer prognosis should be ignored and that heparin therapy should be immediately revisited under this new paradigm. Unlike the suggestions in most previous studies, we propose that heparin use should be reexplored specifically during the interval from initial visualization of a primary tumor until just after its definitive surgical removal. A suggested clinical trial is outlined.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 11885026 [PubMed - indexed for MEDLINE]

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4: Curr Opin Chem Biol. 1999 Dec;3(6):659-64.


Selectin-carbohydrate interactions in shear flow.

Lawrence MB.

Department of Biomedical Engineering, University of Virginia, Health Sciences Center, Box 377, Charlottesville, VA 22908, USA. mbl2a@virginia.edu.

Hydrodynamic shear creates mechanical stresses on selectin bonds, modulating affinity and kinetic parameters. Chemical modification of sialyl Lewis(x) increases the strength of L-selectin bonds without altering recognition, suggesting that mechanical and biorecognition characteristics are separable. L-selectin bond formation rates may be strongly influenced by sulfate orientation in sulfo sialyl Lewis(x).

Publication Types:
Review

PMID: 10600725 [PubMed - indexed for MEDLINE]

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5: Ann Pharm Fr. 1999 May;57(3):216-22.


[Oligosaccharide sulfate inhibitors of selectin-sugar interactions in inflammatory processes]

[Article in French]

Auge C, Dagron F, Lemoine R, Le Narvor C, Lubineau A.

Laboratoire de Chimie Organique Multifonctionnelle, Institut de Chimie Moléculaire d'Orsay, Université Paris-Sud, Orsay.

Leucocyte migration into lymphatic tissues or inflammatory sites depends upon the expression of adhesion molecules. Among these molecules, the selectins expressed on endothelial cells (E- and P-selectins) and leucocytes (L-selectin) recognize carbohydrate ligands such as sialyl Lewis A or sialyl Lewis X oligosaccharides due to the same positioning of NeuAc, Gal and Fuc residues in both isomeric structures. We have shown that the sialic acid residue could be replaced by a sulfate group such as in the sulfated Lewis A pentasaccharide, one of the most potent monovalent ligand for human E-selectin, which was shown to be very active in the prevention of ischemia reperfusion lung injury. In the same way, we have prepared through chemoenzymatic syntheses, two disulfated Lewis X pentasaccharides, the sulfated analogs of carbohydrate ligands found on GLYCAM 1, the natural receptor of L-selectin. Finally, based on the double recognition of L-selectin with Lewis type and glycosaminoglycan structures, we tentatively introduced a possible link between the selectin- and the integrin-mediated lymphocyte adhesion systems.

Publication Types:
English Abstract
Review

PMID: 10427856 [PubMed - indexed for MEDLINE]

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6: Glycoconj J. 1997 Aug;14(5):585-91.


Selectin-carbohydrate interactions during inflammation and metastasis.

McEver RP.

W.K. Warren Medical Research Institute and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA. rodger-mcever@uokhsc.edu

L-, E-, and P-selectin are membrane-anchored, C-type lectins that initiate tethering and rolling of flowing leukocytes on endothelial cells, platelets, or other leukocytes during inflammation. The selectins bind to sialylated, fucosylated, or, in some cases, sulfated glycans on glycoproteins, glycolipids, or proteoglycans. However, they bind with relatively high affinity or avidity to only a few, appropriately modified glycoproteins on leukocytes or endothelial cells. One leukocyte mucin, PSGL-1, tethers flowing leukocytes to P-selectin on activated platelets or endothelial cells, and also helps tether leukocytes to L-selectin on other leukocytes. The physiologic expression of the selectins is tightly controlled to limit the inflammatory response. But dysregulated expression of the selectins may contribute to inflammatory and thrombotic disorders, and perhaps to tumor metastases.

Publication Types:
Review

PMID: 9298691 [PubMed - indexed for MEDLINE]

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7: J Biol Chem. 1995 May 12;270(19):11025-8.


Leukocyte trafficking mediated by selectin-carbohydrate interactions.

McEver RP, Moore KL, Cummings RD.

Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA.

The selectins have attracted intense interest because of their carbohydrate-recognition properties and their pivotal roles in leukocyte trafficking. Future studies will center on the mechanisms for regulating the expression of the selectins and their ligands, the molecular details of selectin binding to glycoprotein ligands and small carbohydrates, and the biophysical principles that selectins employ to mediate attachment and rolling of leukocytes under flow.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 7538108 [PubMed - indexed for MEDLINE]

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8: Adv Exp Med Biol. 1995;376:283-90.


Studies on selectin-carbohydrate interactions.

Jacob GS, Welply JK, Scudder PR, Kirmaier C, Abbas SZ, Howard SC, Keene JL, Schmuke JJ, Broschat K, Steininger C.

Department of Immunology, Searle Discovery Research, Monsanto Company, St. Louis, Missouri 63167, USA.

Recruitment of neutrophils to sites of inflammation is now believed to occur through an initial rolling interaction at the luminal surface of activated endothelium and is mediated by a class of mammalian lectins referred to as the selectins. Selectins recognize carbohydrate determinants on co-receptors. It is generally believed that many selectin molecules must bind to many carbohydrate receptor molecules i.e. multivalent binding, to enable sufficient binding strength to elicit the rolling response between the neutrophil and the endothelial cell. One of the approaches to the generation of more potent molecular antagonists of the selectin-mediated cell-cell interaction is to mimic the multivalent interaction in a single compound. Recent experiments utilising conjugated forms of sialyl Lewisx-BSA have explored this feasibility (Welply et al., 1994). In that study, monovalent sLex (sialic acid alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc), the minimum binding determinant for E-selectin, as well as monovalent sialyllactosamine (sialic acid alpha 2-3Gal beta 1-4GlcNAc), a non-binding structure, and the corresponding multivalent BSA-conjugated forms were tested for their ability to inhibit binding of HL-60 cells to immobilised E-selectin. As expected, only sLex and sLex-BSA were found to do so. sLex16-BSA (16 mol tetrasaccharide/mol BSA) showed a dose-dependent inhibition of HL-60 binding with a measured IC50 of 1 microM; demonstrating close to a three-order of magnitude enhancement of inhibitory activity compared to free sLex. This result indicated that multivalent forms of sLex are capable of binding to E-selectin with higher affinity than do monovalent glycans. In another study, fluorescent forms of monovalent sLex were synthesized and used to measure a true thermodynamic dissociation constant for the monovalent sLex:E-selectin interaction of 120 +/- 31 microM (Jacob et.al., 1995).

Publication Types:
Review

PMID: 8597260 [PubMed - indexed for MEDLINE]

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9: Annu Rev Biochem. 1995;64:113-39.


Selectin-carbohydrate interactions and the initiation of the inflammatory response.

Lasky LA.

Department of Immunology, Genentech Inc., South San Francisco, California 94080, USA.

The orderly migration of various white blood cell types to inflammatory sites is a highly regulated process that involves a diversity of adhesion and signaling molecules. This cellular influx is initiated by relatively low affinity interactions that allow for leukocytes to roll along the vascular surface. This rolling phenomenon is mediated by adhesive interactions between lectin containing adhesion molecules, termed selectins, on both the vascular endothelium and leukocytes, and carbohydrate ligands immobilized on mucin-like scaffolds. This adhesion allows for a rapid recognition of various cell types under the conditions of vascular flow, with the result that inflammatory cells are specifically decelerated adjacent to sites of inflammation. This review focuses on the various biochemical aspects of the interactions between the selectins and their cognate carbohydrate ligands, with an emphasis on the importance of these adhesive events to the inflammatory response.

Publication Types:
Review

PMID: 7574477 [PubMed - indexed for MEDLINE]

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10: Behring Inst Mitt. 1993 Aug;(92):30-5.


Integrins and L-selectin in lymphocyte-endothelium interactions and homing into gut-associated tissue.

Hamann A, Jablonski-Westrich D.

Abteilung für Immunologie, Medizinische Klinik, Universitätskrankenhaus Eppendorf, Hamburg, Germany.

The selective entry of subpopulations and distinct differentiation stages of lymphocytes into different tissues is thought to be mediated by interaction of endothelial ligands with adhesion molecules on lymphocytes. L-selectin has been considered as a peripheral lymph node-specific homing receptor and alpha 4-integrins have been supposed to mediate entry into mucosa-associated lymphoid tissue. In vivo homing studies show that the specificity is not so clear-cut. The MEL-14 antibody indeed blocks almost completely lymphocyte homing into peripheral lymph nodes. However, entry into Peyer's patches and even the intestine itself is also affected. Thus, L-selectin plays a broader part as previously thought. Some antibodies against the alpha 4 and beta 1-integrin chain inhibit selectively lymphocyte homing to Peyer's patches by 50-70%. alpha 4-integrins therefore seem to be important for homing into mucosa-associated tissue, although a considerable fraction of cells does not require this molecule (or this epitope) for recognition of Peyer's patch endothelium. In vitro and in vivo data indicate that neither VCAM-1 nor fibronectin play a role for homing into Peyer's patches; most likely a further ligand recognized by distinct epitopes of alpha 4 is used for recognition of Peyer's patch HEV. A combination of the mAbs MEL-14 and PS/2.3 blocks nearly completely the localization in Peyer's patches. Beside alpha 4-integrins, the beta 2-integrin LFA-1 has been shown to be involved in lymphocyte recirculation. Also combinations of antibodies against LFA-1 and L-selectin as well as of anti LFA-1 with anti alpha 4 show synergistic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 7504455 [PubMed - indexed for MEDLINE]
 

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