Disease relevance of SIGLEC1

• Human rhinoviruses inhibit the accessory function of dendritic cells by inducing sialoadhesin and B7-H1 expression [1].
• Macrophage-tumour cell interactions: identification of MUC1 on breast cancer cells as a potential counter-receptor for the macrophage-restricted receptor, sialoadhesin [2].
• This human-specific loss of T cell Siglec expression associated with T cell hyperactivity may help explain the strikingly disparate prevalence and severity of T cell-mediated diseases such as AIDS and chronic active hepatitis between humans and chimpanzees [3].
• CD33 is a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family of inhibitory receptors and a therapeutic target for acute myeloid leukemia (AML) [4].
• A macrophage marker, Siglec-1, is increased on circulating monocytes in patients with systemic sclerosis and induced by type I interferons and toll-like receptor agonists [5].

Psychiatry related information on SIGLEC1

• We have used Western blotting to examine the expression levels and solubility of alpha SN in brain homogenates from dementia with Lewy bodies (DLB), Parkinson's disease (PD), Alzheimer's disease (AD), and normal controls using samples from the parahippocampus/transentorhinal cortex [6].

High impact information on SIGLEC1

• Crystal structure of the N-terminal domain of sialoadhesin in complex with 3' sialyllactose at 1.85 A resolution [7].
• The p75/AIRM1 gene is located on human chromosome 19 and encodes a novel member of the sialoadhesin family characterized by three immunoglobulin-like extracellular domains (one NH(2)-terminal V-type and two C2-type) and a classical immunoreceptor tyrosine-based inhibitory motif (ITIM) in the cytoplasmic portion [8].
• Similar to other sialoadhesin molecules, p75/AIRM1 appears to mediate sialic acid-dependent ligand recognition [8].
• Recently, research has been carried out to investigate the mannose receptor, the advanced glycosylation end products receptor, the mannose-6-phosphate-receptor, the beta-glucan receptor, sialoadhesin and several galactose-specific binding proteins [9].
• Thus, while soluble MAG-Fc (MAG extracellular domain fused to Fc), a truncated form of MAG-Fc missing Ig-domains 4 and 5, MAG(d1-3)-Fc, and another sialic acid binding protein, sialoadhesin, each bind to neurons in a sialic acid- dependent manner, only full-length MAG-Fc inhibits neurite outgrowth [10].

Biological context of SIGLEC1

• Binding of sialoadhesin to these glycoproteins was sialic acid dependent and was abolished by mutation of a critical residue (R97A) of the sialic acid binding site in the membrane distal Ig-like domain of sialoadhesin [11].
• We have also used ISH and a human-mouse somatic cell hybrid panel to localize the human sialoadhesin gene, SN, to the conserved syntenic region on human chromosome 20p13 [12].
• Like sialoadhesin, CD22 mediates sialic acid-dependent cell adhesion [13].
• In this study, we demonstrate that sialic acid-binding Ig-like lectin 9 (Siglec) represents a surface molecule on neutrophils that is activated by IVIg, resulting in caspase-dependent and caspase-independent forms of cell death [14].
• A homology search of the Drosophila melanogaster and Caenorhabditis elegans genomes suggests that Siglec expression may be limited to animals of deuterostome lineage, coincident with the appearance of the genes of the sialic acid biosynthetic pathway [15].

Anatomical context of SIGLEC1

• In this study, we identify sialoadhesin counterreceptors on T lymphocytes [11].
• CD43 expressed in COS cells supported increased binding to immobilized sialoadhesin [11].
• Sialoadhesin (Siglec-1) is a macrophage-restricted sialic acid-binding receptor that mediates interactions with hemopoietic cells, including lymphocytes [11].
• The expression pattern of human sialoadhesin was found to be similar to that of the mouse receptor, being absent from monocytes and other peripheral blood leukocytes, but expressed strongly by tissue macrophages in the spleen, lymph node, bone marrow, liver, colon, and lungs [16].
• By flow cytometry with peripheral blood leukocytes, recombinant sialoadhesin bound strongly to granulocytes with intermediate binding to monocytes, natural killer cells, B cells, and a subset of CD8 T cells [16].

Associations of SIGLEC1 with chemical compounds

• Using antibodies raised to the recombinant protein, sialoadhesin was immunoprecipitated from the THP-1 human monocytic cell line as an approximate 200-kd glycoprotein [16].
• In conclusion, sialoadhesin specifically recognizes the oligosaccharide sequence Neu5Ac alpha 2----3Gal beta 1----3GalNAc in either sialoglycoproteins or gangliosides [17].
• The past year has provided the X-ray crystal structures of both the N-terminal domain of sialoadhesin and the extracytoplasmic domain of the cation-dependent mannose 6-phosphate receptor [18].
• In contrast, sialoadhesin had less exacting specificity, binding to gangliosides that bear either terminal alpha2,3- or alpha2,8-linked sialic acids with the following rank-order potency of binding: GQ1balpha > GD1a = GD1b = GT1b = GM3 = GM4 > GD3 = GQ1b >> GM1 (nonbinder) [19].
• Thus, while siglecs may not interfere with selectin-mediated recognition, fucosylation could negatively regulate siglec binding [20].

Physical interactions of SIGLEC1

• Finally, sialoadhesin bound different glycoforms of CD43 expressed in Chinese hamster ovary cells, including unbranched (core 1) and branched (core 2) O:-linked glycans, that are normally found on CD43 in resting and activated T cells, respectively [11].
• Related immunoglobulin (Ig) superfamily members either failed to bind gangliosides (CD22) or bound with less stringent specificity (sialoadhesin), whereas a modified form of MAG (bearing three of its five extra-cellular Ig-like domains) bound only GQ1b alpha [21].
• The CD33 antigen is a 67-kd glycosylated transmembrane protein of the sialic acid-binding immunoglobulinlike lectin (siglec) family with immunoreceptor tyrosine-based inhibitory motifs [22].
• Binding specificities of the sialoadhesin family of I-type lectins. Sialic acid linkage and substructure requirements for binding of myelin-associated glycoprotein, Schwann cell myelin protein, and sialoadhesin [19].
• Human Siglec-5 is a sialic acid binding immunoglobulin (Ig)-like lectin (Siglec), comprising one N-terminal IgV-SET domain followed by three IgC2-SET domains, and a cytoplasmic domain with ITIM and SAP motifs which regulate cell signalling [23].

Regulatory relationships of SIGLEC1

• In contrast, expression of inhibitory B7-H1 molecules was up-regulated and R-DC de novo expressed sialoadhesin (Sn) [1].
• Recently, the sialic acid binding activity of the siglec CD22 has been demonstrated to be regulated by sialylation of the CD22 receptor molecule [24].
• Siglec-7 is expressed on natural killer cells and displays unique ligand binding properties different from other members of the Siglec family [25].
• The sialylated MUC1 glycoforms selectively expressed on erythroid cells were able to bind the macrophage-restricted molecule sialoadhesin [26].
• In addition, the ITIMs of CD33-related siglecs can suppress siglec-dependent adhesion of sialylated ligands and mediate endocytosis [27].

Other interactions of SIGLEC1

• Cutting edge: CD43 functions as a T cell counterreceptor for the macrophage adhesion receptor sialoadhesin (Siglec-1) [11].
• The sequence similarity of sialoadhesin to CD22 and related members of the Ig superfamily indicates the existence of a novel family of sialic acid binding proteins involved in cell-cell interactions [13].
• Characterization of CD33 as a new member of the sialoadhesin family of cellular interaction molecules [28].
• The identification of OB-BP1/Siglec-6 as a Siglec family member, coupled with its restricted expression pattern, suggests that it may mediate cell-cell recognition events by interacting with sialylated glycoprotein ligands expressed on specific cell populations [29].
• CD83 is a sialic acid-binding Ig-like lectin (Siglec) adhesion receptor that binds monocytes and a subset of activated CD8+ T cells [30].

Analytical, diagnostic and therapeutic context of SIGLEC1

• Here, we report the molecular cloning, binding properties, and expression pattern of human sialoadhesin [16].
• Low angle shadowing and electron microscopy showed that sialoadhesin consisted of a globular head region of approximately 9 nm and an extended tail of approximately 35 nm [17].
• Characterization of the sialic acid-binding site in sialoadhesin by site-directed mutagenesis [31].
• This result was verified and extended by real-time PCR, showing that a subset of the SSc patients expressed strikingly increased levels of Siglec-1 messenger RNA (mRNA) [5].
• Multiple sequence alignments revealed the presence of this TxYxxV/I motif not only in CD2 subfamily members but also in the cytoplasmic domains of the members of the SHP-2 substrate 1, sialic acid-binding Ig-like lectin, carcinoembryonic Ag, and leukocyte-inhibitory receptor families [32].

References