The Glycosaminoglycan-Binding Domain of Decoy Receptor 3 Is Essential for Induction of Monocyte Adhesion

Abstract

Decoy receptor 3 (DcR3), a soluble receptor for Fas ligand, LIGHT (homologous to lymphotoxins shows inducible expression and competes with HSV glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes), and TNF-like molecule 1A, is highly expressed in cancer cells and in tissues affected by autoimmune disease. DcR3.Fc has been shown to stimulate cell adhesion and to modulate cell activation and differentiation by triggering multiple signaling cascades that are independent of its three known ligands. In this study we found that DcR3.Fc-induced cell adhesion was inhibited by heparin and heparan sulfate, and that DcR3.Fc was unable to bind Chinese hamster ovary K1 mutants defective in glycosaminoglycan (GAG) synthesis. Furthermore, the negatively charged, sulfated GAGs of cell surface proteoglycans, but not their core proteins, were identified as the binding sites for DcR3.Fc. A potential GAG-binding site was found in the C-terminal region of DcR3, and the mutation of three basic residues, i.e., K256, R258, and R259, to alanines abolished its ability to trigger cell adhesion. Moreover, a fusion protein comprising the GAG-binding region of DcR3 with an Fc fragment (DcR3_HBD.Fc) has the same effect as DcR3.Fc in activating protein kinase C and inducing cell adhesion. Compared with wild-type THP-1 cells, cell adhesion induced by DcR3.Fc was significantly reduced in both CD44v3 and syndecan-2 knockdown THP-1 cells. Therefore, we propose a model in which DcR3.Fc may bind to and cross-link proteoglycans to induce monocyte adhesion.

Participation of phosphatidylinositol-3`-kinase on signal transduction through galactosyl-containing glycoprotein receptors of segmentonuclear leukocytes under type 1 diabetes mellitus

“…Імовірно, що цитоплазматичні глікопротеїни з молекулярними масами 34, 30, 22 кДа відповідають азуроцидину, еластазі та катепсину G, функція яких пов'я-зана з бактерицидною та фагоцитарною ак-тивністю лейкоцитів. Виявлене нами зменшення інтенсивності лектинореактивної смуги, яка свідчить про експонування інтегрину p150,95 (CD11c/ CD18), може бути причиною зниження показників агрегації за наявності лектину RСА, оскільки відомо, що активація агрегації НГ відбувається за допомогою приєднання С3b-компонента комплементу до вказаного рецептора [12]. Не виключено також, що пригнічення бактерицидної активності ней-трофілів за умов ЦД 1-го типу, встановлене нами раніше [2], пов'язане зі зниженням вмісту катепсину G, азуроцидину, лейкоци-тарної еластази та рецептора CD88 [10,18,24], молекулярні маси яких відповідають ви-явленим і проаналізованим лектинореактив-ним бендам.…”

Decoy Receptor 3 Expression in AsPC-1 Human Pancreatic Adenocarcinoma Cells via the Phosphatidylinositol 3-Kinase-, Akt-, and NF-κB-Dependent Pathway

“…DcR3 is believed to block the cellular effects caused by the binding of these ligands to their membrane-bound cognate receptors by blocking ligand/receptor binding, as shown for the binding of FasL to Fas and TL1A to death receptor 3 (1,3,4). It has recently been reported that, in addition to binding to these ligands, DcR3 may bind to, and cross-link, proteoglycans to induce monocyte adhesion (5).…”

Galectin-1 Promotes Immunoglobulin Production during Plasma Cell Differentiation

“…Gal-1-Fc or W69G-Fc fusion proteins were overexpressed using the FreeStyle 293 expression system as reported (30). Briefly, 30 g pSecTaggalectin-1-hIgGFc m or pSecTagW69G-hIgGFc m was used to transfect 3 ϫ 10 7 293F cells with 293fectin.…”