Review
Selectins: lectins that initiate cell adhesion under flow

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Abstract

Interactions of selectins with cell-surface glycoconjugates mediate tethering and rolling adhesion of leukocytes and platelets on vascular surfaces. Recent studies have helped elucidate the molecular details of selectin–ligand interactions, the biosynthetic pathways for constructing selectin ligands, and the biophysical and cell biological features that modulate selectin-dependent rolling under flow.

Introduction

The selectins are type I membrane glycoproteins that mediate adhesion of leukocytes and platelets to vascular surfaces 1., 2.. L-selectin is expressed on most leukocytes. E-selectin is expressed on cytokine-activated endothelial cells. P-selectin is rapidly redistributed from membranes of secretory granules to the surfaces of activated platelets and endothelial cells. Each selectin has a membrane-distal C-type lectin domain, followed by an epidermal growth factor (EGF)-like motif, a series of consensus repeats, a transmembrane domain and a short cytoplasmic tail. P- and E-selectin primarily bind to ligands on leukocytes, and P-selectin also interacts with ligands on platelets and some endothelial cells. L-selectin binds to ligands on endothelial cells of high endothelial venules (HEVs) in lymph nodes, on activated endothelial cells and on other leukocytes.

Since their cloning in 1989, the selectins have continued to attract great interest. They are the first group of mammalian lectins shown to mediate cell–cell contact, and the search for their cell-surface glycoconjugate ligands has energized the expanding field of glycobiology. They support rapid and reversible cell adhesion under hydrodynamic flow and have thus attracted bioengineers and other investigators who study the biophysics of cellular interactions. Studies of selectins in animal models have revealed their importance in inflammation, immune responses, hemostasis and wound repair, but also their contributions to diseases as diverse as atherosclerosis, thrombosis, organ transplant rejection, arthritis, sickle cell anemia and tumor metastasis.

This brief review is a selected account of progress in the past year, particularly the characterization of selectin ligands and of mechanisms that selectins use to regulate cell adhesion under flow.

Section snippets

Selectin ligands

Like most lectins, selectins bind to a range of glycoconjugates with varying affinities. Key challenges have been to identify preferred glycoconjugates with higher affinity or avidity for selectins, to elucidate the biosynthetic pathways for selectin ligands, and to determine which glycoconjugates actually mediate cell adhesion to selectins under physiological flow. All selectins bind with low affinity to glycans with terminal components that include α2,3-linked sialic acid and α1,3-linked

Regulation of cell rolling by selectins

Rolling cell adhesion in the vasculature requires the rapid formation and breakage of adhesive bonds that are subjected to applied force [2]. Surface plasmon resonance measurements indicate that the association and dissociation kinetics of unstressed selectin–ligand bonds are rapid, although they vary considerably depending on the selectin and the ligand 30., 31., 32.. The lifetimes of transient leukocyte tethers on low-density selectins shorten in response to increasing wall shear stress. This

Conclusions

Progress continues in elucidating the molecular details of selectin-ligand interactions, although considerable gaps in our understanding remain. This molecular information needs to be integrated with further studies of the biophysical and cell biological features that modulate rolling cell adhesion under hydrodynamic flow.

Update

The work referred to in the text as (T Yago et al., unpublished data) is now in press [50].

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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