Synthetic Glycoprotein Mimics Inhibit L-Selectin-Mediated Rolling and Promote L-Selectin Shedding

Mowery, Patricia; Yang, Zujing; Gordon, Eva J.; Dwir, Oren; Spencer, Andrew; Alon, Ronen; Kiessling, Laura L.

doi:10.1016/j.chembiol.2004.03.027

Cited by 63 publications

(67 citation statements)

References 85 publications

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“…In this article, we present a novel mechanism of L-selectin shedding without any additional chemotactic stimulation. Conversely, Mowery et al (35) incu- Under shear force, L-selectin is cleaved from the cell surface, and the fluorescence intensity of the cell decreases. B, fluorescence intensity of fluorescently labeled neutrophils was measured before and after rolling on a sLe x surface.…”

Section: Discussionmentioning

confidence: 99%

Mechanical Shedding of L-selectin from the Neutrophil Surface during Rolling on Sialyl Lewis x under Flow

Lee

Schultz

Knauf

et al. 2007

Journal of Biological Chemistry

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The interaction of L-selectin expressed on leukocytes with endothelial cells leads to capture and rolling and is critical for the recruitment of leukocytes into sites of inflammation. It is known that leukocyte activation by chemoattractants, the change of osmotic pressure in cell media, or cross-linking of L-selectin all result in rapid shedding of L-selectin. Here we present a novel mechanism for surface cleavage of L-selectin on neutrophils during rolling on a sialyl Lewis x-coated surface that involves mechanical force. Flow cytometry and rolling of neutrophils labeled with Qdot-L-selectin antibodies in an in vitro flow chamber showed that the mechanical shedding of L-selectin occurs during rolling and depends on the amount of shear applied. In addition, the mechanical L-selectin shedding causes an increase in cell rolling velocity with rolling duration, suggesting a gradual loss of L-selectin and is mediated by p38 mitogenactivated protein kinase activation. Thus, these data show that mechanical force induces the cleavage of L-selectin from the neutrophil surface during rolling and therefore decreases the adhesion of cells to a ligand-presenting surface in flow.

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Section: Discussionmentioning

confidence: 99%

Mechanical Shedding of L-selectin from the Neutrophil Surface during Rolling on Sialyl Lewis x under Flow

Lee

Schultz

Knauf

et al. 2007

Journal of Biological Chemistry

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“…2). Ligand density is known to act as a potent driver of shedding (43)(44)(45), and an increasing gradient of HSPG-like ligands across postcapillary venules could therefore influence L-selectin shedding. Also, a lack of shear stress in the subendothelial space could dramatically influence L-selectin clustering and subsequent signaling events that could feedback to activate ADAM17 locally and drive the shedding response specifically in pseudopods.…”

Section: Discussionmentioning

confidence: 99%

L-selectin shedding is activated specifically within transmigrating pseudopods of monocytes to regulate cell polarity in vitro

Rzeniewicz

Newe

Gallardo

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

103

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L-selectin is a cell adhesion molecule that tethers free-flowing leukocytes from the blood to luminal vessel walls, facilitating the initial stages of their emigration from the circulation toward an extravascular inflammatory insult. Following shear-resistant adhesion to the vessel wall, L-selectin has frequently been reported to be rapidly cleaved from the plasma membrane (known as ectodomain shedding), with little knowledge of the timing or functional consequence of this event. Using advanced imaging techniques, we observe L-selectin shedding occurring exclusively as primary human monocytes actively engage in transendothelial migration (TEM). Moreover, the shedding was localized to transmigrating pseudopods within the subendothelial space. By capturing monocytes in midtransmigration, we could monitor the subcellular distribution of L-selectin and better understand how ectodomain shedding might contribute to TEM. Mechanistically, L-selectin loses association with calmodulin (CaM; a negative regulator of shedding) specifically within transmigrating pseudopods. In contrast, L-selectin/ CaM interaction remained intact in nontransmigrated regions of monocytes. We show phosphorylation of L-selectin at Ser 364 is critical for CaM dissociation, which is also restricted to the transmigrating pseudopod. Pharmacological or genetic inhibition of L-selectin shedding significantly increased pseudopodial extensions in transmigrating monocytes, which potentiated invasive behavior during TEM and prevented the establishment of front/back polarity for directional migration persistence once TEM was complete. We conclude that L-selectin shedding directly regulates polarity in transmigrated monocytes, which affirms an active role for this molecule in driving later stages of the multistep adhesion cascade.

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“…[256,257] It appears that cell signaling is important for triggering L-selectin release; [165,258] it is possible that clustering L-selectin activates the signaling cascade that leads to its cleavage; perhaps physiological L-selectin ligands also influence L-selectin levels in vivo. Together, these results suggest that the stoichiometry of Lselectin-ligand interactions is an important determinant of both the adhesive and signaling functions of this protein.…”

Section: 3a B Cell Antigenmentioning

confidence: 99%

Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

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Cell surface receptors acquire information from the extracellular environment and coordinate intracellular responses. Evidence from biochemical and structural studies indicates that many receptors do not operate as individual entities, but rather as part of higher-order complexes (e.g. dimers and oligomers). Coupling the functions of multiple receptors may endow signaling pathways with the sensitivity and malleability required to govern cellular responses. Moreover, multireceptor signaling complexes may provide a means of spatially segregating otherwise degenerate signaling cascades. Despite the proposed importance of receptor-receptor processes in cellular signaling, questions concerning the mechanisms, extent, and consequences of receptor co-localization and interreceptor communication remain unanswered.Chemical synthesis can provide a variety of compounds with which to address the role of receptor assembly in signal transduction. The focus of this review is one such approach -the use of synthetic multivalent ligands to characterize receptor function. Multivalent ligands can be generated that possess a variety of sizes, shapes, valencies, orientations, and densities of binding elements. Their unique architectures imbue multivalent ligands with the ability to access binding modes not available to monovalent compounds. Multivalent ligands, therefore, are capable of illuminating aspects of inter-receptor processes that are not readily probed using conventional approaches. We suggest that, as focus shifts from investigations of the function of individual proteins and toward the analysis of multi-receptor signaling complexes, multivalent ligands will become even more valuable tools with which to ask sophisticated mechanistic questions. Further, multivalent ligands may provide new opportunities for manipulating receptor systems for the deconvolution of pathways, diagnosis, and, ultimately, the treatment of disease.

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Synthetic Glycoprotein Mimics Inhibit L-Selectin-Mediated Rolling and Promote L-Selectin Shedding

Cited by 63 publications

References 85 publications

Mechanical Shedding of L-selectin from the Neutrophil Surface during Rolling on Sialyl Lewis x under Flow

Mechanical Shedding of L-selectin from the Neutrophil Surface during Rolling on Sialyl Lewis x under Flow

L-selectin shedding is activated specifically within transmigrating pseudopods of monocytes to regulate cell polarity in vitro

Synthetic Multivalent Ligands as Probes of Signal Transduction

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