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SIGLEC6
Identifiers
Aliases	SIGLEC6, CD327, CD33L, CD33L1, CD33L2, CDW327, OBBP1, sialic acid binding Ig like lectin 6
External IDs	OMIM: 604405; HomoloGene: 130495; GeneCards: SIGLEC6; OMA:SIGLEC6 - orthologs
Gene location (Human)
Chr.	Chromosome 19 (human)
End	51,531,856 bp
RNA expression pattern
	Top expressed in
	buccal mucosa cell; ; placenta; ; tibialis anterior muscle; ; rectum; ; pancreatic ductal cell; ; gallbladder; ; mucosa of ileum; ; lymph node; ; appendix; ; smooth muscle tissue;
	n/a
	More reference expression data
	n/a
Gene ontology
Molecular function	protein binding; carbohydrate binding;
Cellular component	integral component of membrane; extracellular region; plasma membrane; integral component of plasma membrane; membrane;
Biological process	cell-cell signaling; cell adhesion;
	Sources:Amigo / QuickGO
Orthologs
	946
	n/a
	ENSG00000105492
	n/a
	O43699
	n/a
NM_001177547; NM_001177548; NM_001177549; NM_001245; NM_198845;
	NM_198846
	n/a
NP_001171018; NP_001171019; NP_001171020; NP_001236; NP_942142;
	NP_942143
	n/a
	Wikidata
View/Edit Human

Sialic acid-binding Ig-like lectin 6 is a protein that in humans is encoded by the SIGLEC6 gene.^[3] The gene was originally named CD33L (CD33-like) due to similarities between these genes but later became known as OB-BP1 (OB [leptin]-binding protein 1) due to its ability to bind to this factor and, finally, SIGLEC6 as the sixth member of the SIGLEC family of receptors to be identified.^[4] The protein has also been given the CD designation CD327.^[5]

Expression

Siglec-6 was first found to be expressed in placental tissue,^[3] which was confirmed when this protein was independently identified in a screen for leptin-binding proteins.^[4] Using a newly generated monoclonal antibody against Siglec-6 to detect protein expression, this latter study found that Siglec-6 was expressed by placental cytotrophoblasts and syncytiotrophoblasts as well as several human hematopoietic cell lines, including TF-1, HEL, U937, and THP-1 cells. This monoclonal antibody also bound to nearly all human peripheral blood B cells, although more recent reports have not replicated this finding.^[6] ^[7] Siglec-6 has also been found to be highly expressed on human mast cells, including primary CD34+ progenitor cell-derived mast cells and the LAD2 cell line.^[8] Examining the proteome of mast cells from several tissues, it was determined that Siglec-6 is consistently expressed on mast cells from a variety of human tissues, including adipose, skin, lung, and colon, at relatively high levels.^[7] Siglec-6 was not detected on any peripheral blood leukocytes. Siglec-6 expression on human mast cells has since been extended to those isolated and cultured from skin and the mast cell lines HMC-1.2, LUVA, ROSA KIT^WT, and ROSA KIT^D816V, regardless of KIT mutation status, even when cell-surface expression of the related receptor Siglec-8 is lost.^[9] In addition, single-cell RNAseq of esophageal biopsies from patients with eosinophilic esophagitis or healthy control subjects reveals that SIGLEC6 transcript is only detected in mast cells and not in any other cell types in this tissue.^[9] Other than mast cells, Siglec-6 expression has been detected on exhausted tissue-like B cells^[6] and a minor population of dendritic cells (DCs) known as AXL+ SIGLEC6+ (AS) DCs.^[10] Siglec-6 has also been found on chronic lymphocytic leukemia and acute myeloid leukemia cells and is being explored as a target of CAR T cell therapy.^[11]^[12]^[13]

Ligand binding

Siglec-6 was identified in a screen for leptin-binding proteins, although it interacted with leptin with reduced affinity relative to the leptin receptor.^[4] As a member of the Siglec family of receptors with a conserved arginine residue necessary for sialic acid binding, Siglec-6 was expected to interact with its ligands in a sialic acid-dependent manner. However, leptin is not sialylated,^[14]^[15] and binding to Siglec-6 must therefore be sialic acid independent. The physiological relevance of this interaction has not been determined. Glycodelin A binding to trophoblast cell lines was found to be dependent on sialic acid and competitive with leptin binding.^[16] Glycodelin A co-immunoprecipitated with chimeric Siglec-6-Fc protein in this study, indicating a direct interaction between the proteins, which was also reduced upon the enzymatic removal of sialic acid from glycodelin A. Neither the relevant sialic acid linkage nor the remainder of the glycan structure on glycodelin A necessary for Siglec-6 binding are known. No physiological Siglec-6 ligands with apparent connections to mast cell biology have been identified. Initial studies found that Siglec-6 binds to sialyl-Tn antigen (Neu5Acα2–6GalNAcα) but not to Tn antigen (GalNAcα), 6′-sialyl-lactose (Neu5Acα2–6Galβ1–4Glc), or 3′-sialyl-lactose (Neu5Acα2–3Galβ1–4Glc).^[4] Further characterization of the glycan binding specificity of Siglec-6 revealed that Siglec-6, consistent with other members of the Siglec family, requires the carboxyl group on sialic acid, but is unique in that it does not require the glycolyl group of sialic acid for binding.^[17]

Signaling and function

Siglec-6 contains in its cytoplasmic domain two known signaling motifs identified as an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).^[4] Based on the presence of these motifs, it was presumed that Siglec-6 exerts an inhibitory effect on signaling cascades initiated by an immunoreceptor tyrosine-based activation motif (ITAM)-bearing receptor through the recruitment and activation of protein tyrosine phosphatases like SHP-1/2.

Placental trophoblasts

By introducing mutated versions of Siglec-6 lacking the key tyrosine residues in the ITIM, the ITSM, or both into a trophoblast cell line and treating the cell with the phosphatase inhibitor pervanadate, it was determined that both motifs are capable of being phosphorylated and that Siglec-6 is able to recruit SHP-2 upon phosphorylation of these motifs.^[18] Furthermore, binding of glycodelin A to trophoblast cell lines was found to reduce ERK1/2 phosphorylation, c-Jun protein and mRNA levels, MMP2 and uPA mRNA levels, and invasiveness in a sialic acid- and Siglec-6-dependent manner, suggesting that Siglec-6 reduces trophoblast invasiveness in response to encountering glycodelin A expression in the decidualized endometrium.^[16]

Mast cells

Antibody ligation of Siglec-6 on human CD34+ progenitor-derived mast cells inhibited GM-CSF secretion and slightly reduced degranulation in response to IgE crosslinking, although IL-8 secretion in response to stimulation was not similarly affected.^[19] This observation of Siglec-6 inhibitory function on mast cells was expanded to human skin-derived mast cells and the G protein-coupled receptors MRGPRX2 and C5aR, in addition to the ITAM-bearing FcεRI.^[9] Antibody ligation of Siglec-6 reduced mast cell degranulation in response to lower levels of the stimuli that act through these receptors. However, much more potent inhibition was observed by co-crosslinking Siglec-6 and FcεRI through the use of a secondary crosslinking antibody or the use of streptavidin-based tetramers of antibodies targeting Siglec-6 and FcεRI.^[9] Additionally, the inhibitory effect of Siglec-6 ligation remained for at least 4.5 hours, perhaps due to the observed stability of the receptor on the cell surface following antibody ligation, suggesting that the receptor may continue to participate in inhibitory signaling for prolonged periods of time.

Exhausted tissue-like B cells

Knockdown of SIGLEC6 using siRNA in exhausted tissue-like B cells from HIV-infected individuals enhances the ability of these cells to proliferate or secrete CCL3 or IL-6 upon stimulation.^[6] The lack of known Siglec-6 ligand in this system suggests that Siglec-6 may be reducing responsiveness of these cells through tonic signaling.

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000105492 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b Takei Y, Sasaki S, Fujiwara T, Takahashi E, Muto T, Nakamura Y (1997). "Molecular cloning of a novel gene similar to myeloid antigen CD33 and its specific expression in placenta". Cytogenetic and Genome Research. 78 (3–4): 295–300. doi:10.1159/000134676. PMID 9465907.
^ ^a ^b ^c ^d ^e Patel N, Brinkman-Van der Linden EC, Altmann SW, Gish K, Balasubramanian S, Timans JC, Peterson D, Bell MP, Bazan JF, Varki A, Kastelein RA (August 1999). "OB-BP1/Siglec-6. a leptin- and sialic acid-binding protein of the immunoglobulin superfamily". Journal of Biological Chemistry. 274 (32): 22729–38. doi:10.1074/jbc.274.32.22729. PMID 10428856.
^ Zola H, Swart B, Banham A, Barry S, Beare A, Bensussan A, Boumsell L, Buckley CD, Buhring HJ, Clark G, Engel P, Fox D, Jin BQ, Macardle PJ, Malavasi F, Mason D, Stockinger H, Yang X (January 2007). "CD molecules 2006--human cell differentiation molecules". Journal of Immunological Methods. 319 (1–2): 1–5. doi:10.1016/j.jim.2006.11.001. PMID 17174972.
^ ^a ^b ^c Kardava L, Moir S, Wang W, Ho J, Buckner CM, Posada JG, O'Shea MA, Roby G, Chen J, Sohn HW, Chun TW, Pierce SK, Fauci AS (July 2011). "Attenuation of HIV-associated human B cell exhaustion by siRNA downregulation of inhibitory receptors". Journal of Clinical Investigation. 121 (7): 2614–24. doi:10.1172/JCI45685. PMC 3127436. PMID 21633172.
^ ^a ^b Plum T, Wang X, Rettel M, Krijgsveld J, Feyerabend TB, Rodewald HR (February 2020). "Human Mast Cell Proteome Reveals Unique Lineage, Putative Functions, and Structural Basis for Cell Ablation". Immunity. 52 (2): 404–416. doi:10.1016/j.immuni.2020.01.012. PMID 32049054. S2CID 211086219.
^ Yokoi H, Myers A, Matsumoto K, Crocker PR, Saito H, Bochner BS (June 2006). "Alteration and acquisition of Siglecs during in vitro maturation of CD34+ progenitors into human mast cells". Allergy. 61 (6): 769–76. doi:10.1111/j.1398-9995.2006.01133.x. PMID 16677248. S2CID 21873800.
^ ^a ^b ^c ^d Robida PA, Rische CH, Morgenstern NB-B, Janarthanam R, Cao Y, Krier-Burris RA, Korver W, Xu A, Luu T, Schanin J, Leung J, Rothenberg ME, Wechsler JB, Youngblood BA, Bochner BS, O'Sullivan JA (March 2022). "Functional and Phenotypic Characterization of Siglec-6 on Human Mast Cells". Cells. 11 (7): 1138. doi:10.3390/cells11071138. PMC 8997871. PMID 35406705.
^ Villani AC, Satija R, Reynolds G, Sarkizova S, Shekhar K, Fletcher J, Griesbeck M, Butler A, Zheng S, Lazo S, Jardine L, Dixon D, Stephenson E, Nilsson E, Grundberg I, McDonald D, Filby A, Li W, De Jager PL, Rozenblatt-Rosen O, Lane AA, Haniffa M, Regev A, Hacohen N (April 2017). "Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors". Science. 356 (6335): eaah4573. doi:10.1126/science.aah4573. hdl:1721.1/116797. PMC 5775029. PMID 28428369. S2CID 31380838.
^ Chang J, Peng H, Shaffer BC, Baskar S, Wecken IC, Cyr MG, Martinez GJ, Soden J, Freeth J, Wiestner A, Rader C (September 2018). "Siglec-6 on Chronic Lymphocytic Leukemia Cells Is a Target for Post-Allogeneic Hematopoietic Stem Cell Transplantation Antibodies". Cancer Immunology Research. 6 (9): 1008–1013. doi:10.1158/2326-6066.CIR-18-0102. PMC 6125214. PMID 29980538.
^ Kovalovsky D, Yoon JH, Cyr MG, Simon S, Voynova E, Rader C, Wiestner A, Alejo J, Pittaluga S, Gress RE (September 2021). "Siglec-6 is a target for chimeric antigen receptor T-cell treatment of chronic lymphocytic leukemia". Leukemia. 35 (9): 2581–2591. doi:10.1038/s41375-021-01188-3. PMC 8384967. PMID 33633313. S2CID 232044054.
^ Jetani H, Navarro-Bailon A, Maucher M, Frenz S, Verbruggen C, Yeguas A, Vidriales MB, Gonzalez M, Saborido JR, Kraus S, Mestermann K, Thomas S, Bonig H, Luu M, Monjezi R, Mougiakakos D, Sauer M, Einsele H, Hudacek M (November 2021). "Siglec-6 is a novel target for CAR T-cell therapy in acute myeloid leukemia". Blood. 138 (19): 1830–1842. doi:10.1182/blood.2020009192. PMC 9642786. PMID 34289026. S2CID 236175815.
^ Cohen SL, Halaas JL, Friedman JM, Chait BT, Bennett L, Chang D, Hecht R, Collins F (August 1996). "Human leptin characterization". Nature. 382 (6592): 589. Bibcode:1996Natur.382Q.589C. doi:10.1038/382589a0. PMID 8757126. S2CID 28066268.
^ Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (December 1994). "Positional cloning of the mouse obese gene and its human homologue". Nature. 372 (6505): 425–32. Bibcode:1994Natur.372..425Z. doi:10.1038/372425a0. PMID 7984236. S2CID 4359725.
^ ^a ^b Lam KKW, Chiu PCN, Lee C-L, Pang RTK, Leung CON, Koistinen H, Seppala M, Ho P-C, Yeung WSB (October 2011). "Glycodelin-A protein interacts with Siglec-6 protein to suppress trophoblast invasiveness by down-regulating extracellular signal-regulated kinase (ERK)/c-Jun signaling pathway". Journal of Biological Chemistry. 286 (43): 37118–27. doi:10.1074/jbc.M111.233841. PMC 3199459. PMID 21880722.
^ Brinkman-Van der Linden EC, Varki A (March 2000). "New aspects of siglec binding specificities, including the significance of fucosylation and of the sialyl-Tn epitope. Sialic acid-binding immunoglobulin superfamily lectins". Journal of Biological Chemistry. 275 (12): 8625–32. doi:10.1074/jbc.275.12.8625. PMID 10722702.
^ Stefanski AL, Renecle MD, Rumer KK, Winn VD (March 2014). "Siglec-6 phosphorylation at intracellular tyrosine residues leads to the recruitment of SHP-2 phosphatase". Reproductive Sciences. 21 (3): 388A.
^ Yu Y, Blokhuis BRJ, Diks MAP, Keshavarzian A, Garssen J, Redegeld FA (September 2018). "Functional Inhibitory Siglec-6 Is Upregulated in Human Colorectal Cancer-Associated Mast Cells". Frontiers in Immunology. 9: 2138. doi:10.3389/fimmu.2018.02138. PMC 6159741. PMID 30294327.

External links

SIGLEC6+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000105492 – Ensembl, May 2017

[2] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid9465907-3] Takei Y, Sasaki S, Fujiwara T, Takahashi E, Muto T, Nakamura Y (1997). "Molecular cloning of a novel gene similar to myeloid antigen CD33 and its specific expression in placenta". Cytogenetic and Genome Research. 78 (3–4): 295–300. doi:10.1159/000134676. PMID 9465907.

[pmid10428856-4] Patel N, Brinkman-Van der Linden EC, Altmann SW, Gish K, Balasubramanian S, Timans JC, Peterson D, Bell MP, Bazan JF, Varki A, Kastelein RA (August 1999). "OB-BP1/Siglec-6. a leptin- and sialic acid-binding protein of the immunoglobulin superfamily". Journal of Biological Chemistry. 274 (32): 22729–38. doi:10.1074/jbc.274.32.22729. PMID 10428856.

[pmid17174972-5] Zola H, Swart B, Banham A, Barry S, Beare A, Bensussan A, Boumsell L, Buckley CD, Buhring HJ, Clark G, Engel P, Fox D, Jin BQ, Macardle PJ, Malavasi F, Mason D, Stockinger H, Yang X (January 2007). "CD molecules 2006--human cell differentiation molecules". Journal of Immunological Methods. 319 (1–2): 1–5. doi:10.1016/j.jim.2006.11.001. PMID 17174972.

[pmid21633172-6] Kardava L, Moir S, Wang W, Ho J, Buckner CM, Posada JG, O'Shea MA, Roby G, Chen J, Sohn HW, Chun TW, Pierce SK, Fauci AS (July 2011). "Attenuation of HIV-associated human B cell exhaustion by siRNA downregulation of inhibitory receptors". Journal of Clinical Investigation. 121 (7): 2614–24. doi:10.1172/JCI45685. PMC 3127436. PMID 21633172.

[pmid32049054-7] Plum T, Wang X, Rettel M, Krijgsveld J, Feyerabend TB, Rodewald HR (February 2020). "Human Mast Cell Proteome Reveals Unique Lineage, Putative Functions, and Structural Basis for Cell Ablation". Immunity. 52 (2): 404–416. doi:10.1016/j.immuni.2020.01.012. PMID 32049054. S2CID 211086219.

[pmid16677248-8] Yokoi H, Myers A, Matsumoto K, Crocker PR, Saito H, Bochner BS (June 2006). "Alteration and acquisition of Siglecs during in vitro maturation of CD34+ progenitors into human mast cells". Allergy. 61 (6): 769–76. doi:10.1111/j.1398-9995.2006.01133.x. PMID 16677248. S2CID 21873800.

[cells11071138-9] Robida PA, Rische CH, Morgenstern NB-B, Janarthanam R, Cao Y, Krier-Burris RA, Korver W, Xu A, Luu T, Schanin J, Leung J, Rothenberg ME, Wechsler JB, Youngblood BA, Bochner BS, O'Sullivan JA (March 2022). "Functional and Phenotypic Characterization of Siglec-6 on Human Mast Cells". Cells. 11 (7): 1138. doi:10.3390/cells11071138. PMC 8997871. PMID 35406705.

[pmid28428369-10] Villani AC, Satija R, Reynolds G, Sarkizova S, Shekhar K, Fletcher J, Griesbeck M, Butler A, Zheng S, Lazo S, Jardine L, Dixon D, Stephenson E, Nilsson E, Grundberg I, McDonald D, Filby A, Li W, De Jager PL, Rozenblatt-Rosen O, Lane AA, Haniffa M, Regev A, Hacohen N (April 2017). "Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors". Science. 356 (6335): eaah4573. doi:10.1126/science.aah4573. hdl:1721.1/116797. PMC 5775029. PMID 28428369. S2CID 31380838.

[pmid29980538-11] Chang J, Peng H, Shaffer BC, Baskar S, Wecken IC, Cyr MG, Martinez GJ, Soden J, Freeth J, Wiestner A, Rader C (September 2018). "Siglec-6 on Chronic Lymphocytic Leukemia Cells Is a Target for Post-Allogeneic Hematopoietic Stem Cell Transplantation Antibodies". Cancer Immunology Research. 6 (9): 1008–1013. doi:10.1158/2326-6066.CIR-18-0102. PMC 6125214. PMID 29980538.

[pmid33633313-12] Kovalovsky D, Yoon JH, Cyr MG, Simon S, Voynova E, Rader C, Wiestner A, Alejo J, Pittaluga S, Gress RE (September 2021). "Siglec-6 is a target for chimeric antigen receptor T-cell treatment of chronic lymphocytic leukemia". Leukemia. 35 (9): 2581–2591. doi:10.1038/s41375-021-01188-3. PMC 8384967. PMID 33633313. S2CID 232044054.

[pmid34289026-13] Jetani H, Navarro-Bailon A, Maucher M, Frenz S, Verbruggen C, Yeguas A, Vidriales MB, Gonzalez M, Saborido JR, Kraus S, Mestermann K, Thomas S, Bonig H, Luu M, Monjezi R, Mougiakakos D, Sauer M, Einsele H, Hudacek M (November 2021). "Siglec-6 is a novel target for CAR T-cell therapy in acute myeloid leukemia". Blood. 138 (19): 1830–1842. doi:10.1182/blood.2020009192. PMC 9642786. PMID 34289026. S2CID 236175815.

[pmid8757126-14] Cohen SL, Halaas JL, Friedman JM, Chait BT, Bennett L, Chang D, Hecht R, Collins F (August 1996). "Human leptin characterization". Nature. 382 (6592): 589. Bibcode:1996Natur.382Q.589C. doi:10.1038/382589a0. PMID 8757126. S2CID 28066268.

[pmid7984236-15] Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (December 1994). "Positional cloning of the mouse obese gene and its human homologue". Nature. 372 (6505): 425–32. Bibcode:1994Natur.372..425Z. doi:10.1038/372425a0. PMID 7984236. S2CID 4359725.

[pmid21880722-16] Lam KKW, Chiu PCN, Lee C-L, Pang RTK, Leung CON, Koistinen H, Seppala M, Ho P-C, Yeung WSB (October 2011). "Glycodelin-A protein interacts with Siglec-6 protein to suppress trophoblast invasiveness by down-regulating extracellular signal-regulated kinase (ERK)/c-Jun signaling pathway". Journal of Biological Chemistry. 286 (43): 37118–27. doi:10.1074/jbc.M111.233841. PMC 3199459. PMID 21880722.

[pmid10722702-17] Brinkman-Van der Linden EC, Varki A (March 2000). "New aspects of siglec binding specificities, including the significance of fucosylation and of the sialyl-Tn epitope. Sialic acid-binding immunoglobulin superfamily lectins". Journal of Biological Chemistry. 275 (12): 8625–32. doi:10.1074/jbc.275.12.8625. PMID 10722702.

[ReprodSciAbstract-18] Stefanski AL, Renecle MD, Rumer KK, Winn VD (March 2014). "Siglec-6 phosphorylation at intracellular tyrosine residues leads to the recruitment of SHP-2 phosphatase". Reproductive Sciences. 21 (3): 388A.

[pmid30294327-19] Yu Y, Blokhuis BRJ, Diks MAP, Keshavarzian A, Garssen J, Redegeld FA (September 2018). "Functional Inhibitory Siglec-6 Is Upregulated in Human Colorectal Cancer-Associated Mast Cells". Frontiers in Immunology. 9: 2138. doi:10.3389/fimmu.2018.02138. PMC 6159741. PMID 30294327.

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PROFILPELAJAR.COM

SIGLEC6

Expression

Ligand binding

Signaling and function

Placental trophoblasts

Mast cells

Exhausted tissue-like B cells

References

External links

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