Monosialogangliosides of Human Myelogenous Leukemia HL60 Cells and Normal Human Leukocytes. 2. Characterization of E-Selectin Binding Fractions, and Structural Requirements for Physiological Binding to E-Selectin

Stroud, Mark R.; Handa, Kazuko; Salyan, Mary Ellen K.; Itô, Kazunori; Levery, Steven B.; Hakomori, Sen‐itiroh; Reinhold, Bruce B.; Reinhold, Vernon N.

doi:10.1021/bi952461g

Cited by 110 publications

(65 citation statements)

References 29 publications

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“…The monosialogangliosides detected in the high mass region (above m/z 5 3000) consisted of sialylated lactosylceramides with 4 to 6 LacNAc repeats and multiple internal fucoses as expected on putative selectin ligands 11,38 (supplemental epitope was also detected (supplemental Figure 8A-B). No glycans were detected in the nonpolar GSL fraction (data not shown).…”

Section: St3gal-4 Controls Sle X Expression On O-and N-glycansmentioning

confidence: 70%

“…9,10 Thus, protease-insensitive gangliosides may be physiological E-selectin ligands that are unique to humans. 11 Among the a1,3fucosyltransferases, the enzyme FUT9 reportedly plays a more significant role during human leukocyte adhesion, compared with FUT7 and FUT4 which are the dominant players in mice. 8 Among additional differences, L-selectin in human but not mouse neutrophils are considered to act as an E-selectin ligand, 12 though its relative roles in direct E-selectin binding vs secondary neutrophil-neutrophil adhesion remains unresolved.…”

Section: Introductionmentioning

confidence: 99%

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ST3Gal-4 is the primary sialyltransferase regulating the synthesis of E-, P-, and L-selectin ligands on human myeloid leukocytes

Mondal

Buffone

Stolfa

et al. 2015

Blood

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• A single a(2,3) sialyltransferase, ST3Gal-4, controls sLe X biosynthesis on N-and O-glycans in cells of human myeloid lineage.• Blocking this enzyme activity prevents human neutrophil adhesion to E-, P-, and L-selectin.The precise glycosyltransferase enzymes that mediate selectin-ligand biosynthesis in human leukocytes are unknown. This knowledge is important because selectin-mediated cell tethering and rolling is a critical component of both normal immune response and various vascular disorders. We evaluated the role of 3 a(2,3)sialyltransferases, ST3Gal-3, -4, and -6, which act on the type II N-Acetyllactosamine structure (Galb1,4GlcNAc) to create sialyl Lewis-X (sLe X ) and related sialofucosylated glycans on human leukocytes of myeloid lineage. These genes were either silenced using lentiviral short hairpin RNA (shRNA) or functionally ablated using the clustered regularly interspaced short palindromic repeat/ Cas9 technology. The results show that ST3Gal-4, but not ST3Gal-3 or -6, is the major sialyltransferase regulating the biosynthesis of E-, P-, and L-selectin ligands in humans. Reduction in ST3Gal-4 activity lowered cell-surface HECA-452 epitope expression by 75% to 95%. Glycomics profiling of knockouts demonstrate an almost complete loss of the sLe X epitope on both leukocyte N-and O-glycans. In cell-adhesion studies, ST3Gal-4 knockdown/knockout cells displayed 90% to 100% reduction in tethering and rolling density on all selectins. ST3Gal-4 silencing in neutrophils derived from human CD34 1 hematopoietic stem cells also resulted in 80% to 90% reduction in cell adhesion to all selectins. Overall, a single sialyltransferase regulates selectin-ligand biosynthesis in human leukocytes, unlike mice where multiple enzymes contribute to this function. (Blood. 2015;125(4):687-696)

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Section: St3gal-4 Controls Sle X Expression On O-and N-glycansmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

ST3Gal-4 is the primary sialyltransferase regulating the synthesis of E-, P-, and L-selectin ligands on human myeloid leukocytes

Mondal

Buffone

Stolfa

et al. 2015

Blood

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“…The ''myeloglycan'' epitope (see Table 1 for structure) found originally in GSLs (35,36) may well be present in O-linked form in PSGL-1 and other mucin-type glycoproteins. Thus, type 2 glycosynapses may play major roles in glycosylationdependent adhesion through selectins and siglecs, and consequent changes in signaling leading to phenotypic changes, e.g., tumor cell invasiveness.…”

Section: Type 2 Glycosynapse: O-linked Mucin-type Adhesion Epitopes Omentioning

confidence: 99%

The glycosynapse

Hakomori

2002

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

Self Cite

472

217

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Physically distinguishable microdomains associated with various functional membrane proteins are one of the major current topics in cell biology. Glycosphingolipids present in such microdomains have been used as “markers;” however, the functional role of glycosyl epitopes in microdomains has received little attention. In this review, I have tried to summarize the evidence that glycosyl epitopes in microdomains mediate cell adhesion and signal transduction events that affect cellular phenotypes. Molecular assemblies that perform such functions are hereby termed “glycosynapse” in analogy to “immunological synapse,” the membrane assembly of immunocyte adhesion and signaling. Three types of glycosynapses are so far distinguishable: (i) Glycosphingolipids organized with cytoplasmic signal transducers and proteolipid tetraspanin with or without growth factor receptors; (ii) transmembrane mucin-type glycoproteins with clustered O-linked glycoepitopes for cell adhesion and associated signal transducers at lipid domain; and (iii) N-glycosylated transmembrane adhesion receptors complexed with tetraspanin and gangliosides, as typically seen with the integrin–tetraspanin–ganglioside complex. The possibility is discussed that glycosynapses give rise to a high degree of diversity and complexity of phenotypes

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“…1). sLe x is a peripheral carbohydrate structure generated by the sequential action of various glycosyltransferases and can be found linked to different types of glycoconjugates, such as O-glycans (6), complex N-glycans (8,9), or glycolipids (10).…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

Sialyl-Lewisx on P-Selectin Glycoprotein Ligand-1 Is Regulated during Differentiation and Maturation of Dendritic Cells: A Mechanism Involving the Glycosyltransferases C2GnT1 and ST3Gal I

Julien

Grimshaw

Sutton-Smith

et al. 2007

The Journal of Immunology

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To fulfil their function as APCs, dendritic cells (DC) and their precursors need to travel from blood to the peripheral tissues and, upon activation, migrate from tissues to draining lymph nodes. Because O-glycans play a role in T cell trafficking, we investigated the O-glycosylation profile of human monocyte-derived DC. Sialyl-Lewisx (sLex), a glycan involved in extravasation via selectin binding, was found to be expressed exclusively on P-selectin glycoprotein ligand-1 in monocytes and immature DC. However, sLex was lost from mature DC even though these cells retained expression of P-selectin glycoprotein ligand-1. Maturation of DC led to a rapid change in the expression of glycosyltransferases involved in O-linked glycosylation. A down-regulation of C2GnT1 mRNA and enzymatic activity was observed with a concurrent up-regulation of ST3Gal I and ST6GalNAc II mRNA resulting in a loss of the core 2 structures required for sLex expression as a P-selectin ligand. Interestingly, the early regulation of these glycosyltransferases was mediated by PGE2, which is known to be required for human DC migration. The pattern of O-glycosylation seen in mature cells was very similar to that expressed by naive T cells, which home to lymph nodes. Our data show that the regulation of O-glycosylation controls sLex expression, and also suggest that O-glycans may have a function in DC migration.

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Monosialogangliosides of Human Myelogenous Leukemia HL60 Cells and Normal Human Leukocytes. 2. Characterization of E-Selectin Binding Fractions, and Structural Requirements for Physiological Binding to E-Selectin

Cited by 110 publications

References 29 publications

ST3Gal-4 is the primary sialyltransferase regulating the synthesis of E-, P-, and L-selectin ligands on human myeloid leukocytes

ST3Gal-4 is the primary sialyltransferase regulating the synthesis of E-, P-, and L-selectin ligands on human myeloid leukocytes

The glycosynapse

Sialyl-Lewisx on P-Selectin Glycoprotein Ligand-1 Is Regulated during Differentiation and Maturation of Dendritic Cells: A Mechanism Involving the Glycosyltransferases C2GnT1 and ST3Gal I

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