SIGLEC6

What is SIGLEC6 protein?

SIGLEC6 gene (sialic acid binding Ig like lectin 6) is a protein coding gene which situated on the long arm of chromosome 19 at locus 19q13. SIGLEC6, also known as CD327 or OB-BP1, is a cell surface receptor that belongs to the SIGLEC family. It is an immunomodulatory protein that is mainly expressed on immune cells such as macrophages, dendritic cells, natural killer cells, T cells, and B cells. SIGLEC6 has an immunoreceptor tyrosine motif inhibitory domain (ITIM) that regulates the immune response by interacting with tyrosine kinases within cells. SIGLEC6 functions include cell adhesion, intercellular recognition, and immune signaling. SIGLEC6 expression is also associated with placental function and is up-regulated in preeclampsia. The SIGLEC6 protein is consisted of 453 amino acids and SIGLEC6 molecular weight is approximately 49.9 kDa.

What is the function of SIGLEC6 protein?

SIGLEC6 is a putative adhesion molecule capable of mediating intercellular binding through sialic acid-dependent mechanisms. SIGLEC6 contains an immunoreceptor tyrosine motif inhibitory domain (ITIM) that regulates the immune response by interacting with tyrosine kinases within cells. Activation of SIGLEC6 can reduce inflammatory responses by inhibiting the activation of immune cells, for example, its expression on mast cells can regulate mast cell activation. SIGLEC6 mediates uptake of extracellular vesicles, possibly through atypical glycolipid binding pockets.

Fig1. Schema showing the mechanism of sTn-mediated Siglec-6 dependent migration of Siglec-6+ cells. (Jessica Nunes, 2024)

SIGLEC6 Related Signaling Pathway

SIGLEC6 can be used as a cell adhesion molecule to promote intercellular binding through sialic acid-dependent means, and participate in cell recognition and maintenance of tissue structure. SIGLEC6 contains the immunoreceptor tyrosine motif inhibitory domain (ITIM), which can regulate the activation and inhibition of immune cells through interaction with intracellular tyrosine kinases, affecting the immune response. SIGLEC6 may participate in the regulation of inflammatory response by regulating the activity of immune cells, and affect the pathological process of allergic diseases and inflammatory diseases. SIGLEC6 is expressed in certain types of cancer and may be involved in tumor aggressiveness, metastasis, and immune escape. For example, in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), SIGLEC6 can be used as a target for CAR T cell therapy to target and inhibit tumor cell growth through specific CAR T cells.

SIGLEC6 Related Diseases

SIGLEC6 is an immunomodulatory protein whose abnormal expression is associated with a variety of diseases. In the field of cancer, SIGLEC6 expression is associated with chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and certain types of solid tumors (such as bladder cancer), and may promote tumor progression and metastasis by influencing immune cell activity in the tumor microenvironment. In addition, SIGLEC6 also plays a role in autoimmune diseases, such as in allergic diseases, SIGLEC6 acts as an inhibitory receptor on mast cells, and its activation may help regulate mast cell activation and degranulation, thereby affecting the occurrence of allergic diseases. SIGLEC6 also plays a role in pregnancy-related disorders, such as preeclampsia, whose expression is upregulated in the placenta and may be involved in the development of the disease.

Bioapplications of SIGLEC6

The regulatory role of SIGLEC6 makes it a target for drug development, and it may be beneficial for the treatment of related diseases by developing small molecule drugs or biologics that can regulate the activity of SIGLEC6. The expression level of SIGLEC6 may vary in different diseases and can be used as a biomarker for disease diagnosis, prognosis assessment and treatment response monitoring. In the field of cell therapy, such as CAR-T cell therapy, SIGLEC6 can be used as a specific marker for specific cell types to help improve the targeting and effectiveness of therapy. What's more, its manifestation in the disease makes it a potential therapeutic target.

Case Study 1: Edward N Schmidt, 2023

Immunomodulatory Siglecs are controlled by their glycoprotein and glycolipid ligands. Siglec-glycolipid interactions are often studied outside the context of a lipid bilayer, missing the complex behaviors of glycolipids in a membrane. Through optimizing a liposomal formulation to dissect Siglec-glycolipid interactions, it is shown that Siglec-6 can recognize glycolipids independent of its canonical binding pocket, suggesting that Siglec-6 possesses a secondary binding pocket tailored for recognizing glycolipids in a bilayer. A panel of synthetic neoglycolipids is used to probe the specificity of this glycolipid binding pocket on Siglec-6, leading to the development of a neoglycolipid with higher avidity for Siglec-6 compared to natural glycolipids. This neoglycolipid facilitates the delivery of liposomes to Siglec-6 on human mast cells, memory B-cells and placental syncytiotrophoblasts. A physiological relevance for glycolipid recognition by Siglec-6 is revealed for the binding and internalization of extracellular vesicles.

Fig1. Binding of liposomes formulated with 3 mol% 3 and 4 to WT Siglec-6 CHO cells in the cell assay, relative to liposomes formulated without a ligand.

Fig2. Binding of 5 nGLLs to CHO cells expressing each Siglec-6/8 chimera.

Case Study 2: Kevin K W Lam, 2011

Glycodelin-A (GdA) is abundantly synthesized by the decidua but not the trophoblast. Previous data indicate that GdA suppresses the invasion of trophoblast cell lines by down-regulating proteinase expression and activities. This study addresses the signaling pathway involved in the above phenomenon. GdA was found to suppress phosphorylation of ERKs and expression of their downstream effector c-Jun, a component of the transcription factor activator protein-1 (AP-1). The involvement of ERKs and c-Jun in suppressing trophoblast invasion and biosynthesis of proteinases was confirmed by using siRNA knockdown and pharmacological inhibitors. Co-immunoprecipitation showed that Siglec-6 on the trophoblast was the binding protein of GdA. The binding of GdA to Siglec-6 was sialic acid-dependent. Treatment with anti-Siglec-5 antibody abolished the invasion suppressive activities of GdA.

Fig3. Western blot analysis of the interaction between recombinant Siglec-6 chimeric protein and either GdA or desialylated GdA.

Fig4. Effect of Siglec-6 antibody on JEG-3 cell invasion.

SIGLEC6 has several biochemical functions, for example, carbohydrate binding,protein binding. Some of the functions are cooperated with other proteins, some of the functions could acted by SIGLEC6 itself. We selected most functions SIGLEC6 had, and list some proteins which have the same functions with SIGLEC6. You can find most of the proteins on our site.

SIGLEC6 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with SIGLEC6 here. Most of them are supplied by our site. Hope this information will be useful for your research of SIGLEC6.

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