Assembly, organization and regulation of cell-surface receptors by lectin–glycan complexes

2015 ◽  
Vol 469 (1) ◽  
pp. 1-16 ◽  
Author(s):  
María T. Elola ◽  
Ada G. Blidner ◽  
Fátima Ferragut ◽  
Candelaria Bracalente ◽  
Gabriel A. Rabinovich
Keyword(s):  
Cell Surface ◽  
Protein Interactions ◽  
Consensus Sequence ◽  
Hierarchical Organization ◽  
Receptor Expression ◽  
Receptor Internalization ◽  
Local Concentration ◽  
Surface Receptors ◽  
Extracellular Milieu ◽  
Galectin 3

Galectins are a family of β-galactoside-binding lectins carrying at least one consensus sequence in the carbohydrate-recognition domain. Properties of glycosylated ligands, such as N- and O-glycan branching, LacNAc (N-acetyl-lactosamine) content and the balance of α2,3- and α2,6-linked sialic acid dramatically influence galectin binding to a preferential set of counter-receptors. The presentation of specific glycans in galectin-binding partners is also critical, as proper orientation and clustering of oligosaccharide ligands on multiple carbohydrate side chains increase the binding avidity of galectins for particular glycosylated receptors. When galectins are released from the cells, they typically concentrate on the cell surface and the local matrix, raising their local concentration. Thus galectins can form their own multimers in the extracellular milieu, which in turn cross-link glycoconjugates on the cell surface generating galectin–glycan complexes that modulate intracellular signalling pathways, thus regulating cellular processes such as apoptosis, proliferation, migration and angiogenesis. Subtle changes in receptor expression, rates of protein synthesis, activities of Golgi enzymes, metabolite concentrations supporting glycan biosynthesis, density of glycans, strength of protein–protein interactions at the plasma membrane and stoichiometry may modify galectin–glycan complexes. Although galectins are key contributors to the formation of these extended glycan complexes leading to promotion of receptor segregation/clustering, and inhibition of receptor internalization by surface retention, when these complexes are disrupted, some galectins, particularly galectin-3 and -4, showed the ability to drive clathrin-independent mechanisms of endocytosis. In the present review, we summarize the data available on the assembly, hierarchical organization and regulation of conspicuous galectin–glycan complexes, and their implications in health and disease.

scholarly journals Regulation of cell-surface receptors for human interferon-γ on the human histiocytic lymphoma cell line U937

1991 ◽  
Vol 274 (3) ◽  
pp. 775-780 ◽  
Author(s):  
D S Finbloom
Keyword(s):  
Cell Surface ◽  
Cell Line ◽  
Specific Radioactivity ◽  
Receptor Expression ◽  
Cell Surface Expression ◽  
Cell Surface Receptors ◽  
Minor Role ◽  
Ifn Gamma ◽  
Surface Receptors ◽  
High Specific Radioactivity

Interferon-gamma (IFN gamma) binds to high-affinity receptors on monocytes and is rapidly internalized. This study investigates the ability of the human monocyte-like cell line, U937, to regulate the cell-surface expression of the IFN gamma receptor (IFN gamma R) during endocytosis of ligand. Recombinant IFN gamma was radiolabelled to high specific radioactivity with Bolton-Hunter reagent and used to enumerate IFN gamma R on treated U937 cells. Cells which had internalized IFN gamma for up to 3 h displayed maximal levels of IFN gamma R at all time points tested after all unlabelled IFN gamma had been acid-stripped from the cell at pH 2.78. Therefore there was no evidence of down-modulation of the receptor. After trypsin treatment of the IFN gamma R, the cells were able to synthesize and insert into the cell membrane up to 1000 IFN gamma R molecules/h after a 60 min lag. Since biosynthesis played a minor role during the first 30 min of endocytosis, I examined other possibilities to explain the lack of down-modulation of the receptor. A solubilized-receptor assay revealed the presence of an intracellular pool of receptors equal to about 25% of the number of cell surface receptors. Using trypsin to differentiate between intracellular and surface receptors, I observed that 43% of those receptors that were internalized after a 30 min exposure to IFN gamma (580 molecules) could be recycled back to the plasma membrane. In addition, equal rates of receptor decay (t1/2 = 5 h) were observed in the presence of cycloheximide with or without IFN gamma. All the data taken together suggest that during the first 30 min of endocytosis both the expression of an intracellular source of receptor and recycling of internalized receptors contribute to maintain optimal receptor expression.

scholarly journals Somatostatin-Induced Regulation of SST2A Receptor Expression and Cell Surface Availability in Central Neurons: Role of Receptor Internalization

2000 ◽  
Vol 20 (16) ◽  
pp. 5932-5939 ◽  
Author(s):  
Hélène Boudin ◽  
Philippe Sarret ◽  
Jean Mazella ◽  
Agnes Schonbrunn ◽  
Alain Beaudet
Keyword(s):  
Cell Surface ◽  
Receptor Expression ◽  
Receptor Internalization ◽  
Central Neurons

scholarly journals Sulfated polysaccharides identified as inducers of neuropilin-1 internalization and functional inhibition of VEGF165 and semaphorin3A

Blood ◽  
2008 ◽  
Vol 111 (8) ◽  
pp. 4126-4136 ◽  
Author(s):  
Masashi Narazaki ◽  
Marta Segarra ◽  
Giovanna Tosato
Keyword(s):  
Cell Surface ◽  
Dextran Sulfate ◽  
Receptor Internalization ◽  
Sulfated Polysaccharides ◽  
Cell Surface Receptors ◽  
Ligand Interaction ◽  
Surface Receptors ◽  
Neuropilin 1

Abstract Neuropilin-1 (NRP1) and NRP2 are cell surface receptors shared by class 3 semaphorins and vascular endothelial growth factor (VEGF). Ligand interaction with NRPs selects the specific signal transducer, plexins for semaphorins or VEGF receptors for VEGF, and promotes NRP internalization, which effectively shuts down receptor-mediated signaling by a second ligand. Here, we show that the sulfated polysaccharides dextran sulfate and fucoidan, but not others, reduce endothelial cell-surface levels of NRP1, NRP2, and to a lesser extent VEGFR-1 and VEGFR-2, and block the binding and in vitro function of semaphorin3A and VEGF165. Administration of fucoidan to mice reduces VEGF165-induced angiogenesis and tumor neovascularization in vivo. We find that dextran sulfate and fucoidan can bridge the extracellular domain of NRP1 to that of the scavenger receptor expressed by endothelial cells I (SREC-I), and induce NRP1 and SREC-I coordinate internalization and trafficking to the lysosomes. Overexpression of SREC-I in SREC-I–negative cells specifically reduces cell-surface levels of NRP1, indicating that SREC-I mediates NRP1 internalization. These results demonstrate that engineered receptor internalization is an effective strategy for reducing levels and function of cell-surface receptors, and identify certain sulfated polysaccharides as “internalization inducers.”

scholarly journals Prolonged defects of interleukin-2 production, responsiveness, and receptor expression in patients with acute lymphoblastic leukemia

Blood ◽  
1989 ◽  
Vol 73 (6) ◽  
pp. 1608-1614
Author(s):  
MS Borzy ◽  
D Ridgway
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cell Surface ◽  
Lymphoblastic Leukemia ◽  
Interleukin 2 ◽  
Receptor Expression ◽  
Cell Surface Receptors ◽  
Con A ◽  
Surface Receptors ◽  
Control Subjects ◽  
Patient Groups

The proliferative responsiveness to, production of, and the expression of cell-surface receptors for interleukin-2 (IL-2) were examined in 14 children with acute lymphoblastic leukemia (ALL) in remission and receiving maintenance chemotherapy for 6 to 35 months; in 19 children with ALL in remission and off all therapy for 2 to 138 months; and 15 control subjects. Short-term concanavalin A (Con A)-activated, purified T lymphocytes from patients on, as well as patients off, therapy had a significantly decreased proliferative responsiveness to a saturating amount of exogenous, recombinant IL-2 as compared to control subjects (P less than 0.005 and less than 0.05, respectively). Phytohemagglutinin (PHA)-stimulated IL-2 production by peripheral blood mononuclear cells (PBMC) was also substantially decreased in both patient groups with the median values of IL-2 produced being 2.2, 2.1, and 8.1 U/mL in the on therapy, off therapy, and control groups, respectively. In addition, PHA-induced expression of cell-surface receptors for IL-2 on PBMC was significantly decreased in both patient groups as compared to control subjects (P less than 0.01). Lymphocyte proliferation to mitogens (PHA, Con A, and pokeweed mitogen) was similar in all three groups studied. These results demonstrate that substantial quantitative and qualitative abnormalities of the IL-2-T lymphocyte system are present in the majority of treated patients with ALL, not only during maintenance therapy, but also for a prolonged period after the cessation of all chemotherapy. These long-lasting defects of the IL-2 system are most likely a late effect of chemotherapy and may result in increased complications in some long- term survivors of ALL.

Modulation of signalling initiated by phosphoinositidase-C-linked receptors

1993 ◽  
Vol 184 (1) ◽  
pp. 145-159
Author(s):  
R. J. Wojcikiewicz ◽  
S. R. Nahorski
Keyword(s):  
Cell Surface ◽  
Second Messengers ◽  
Receptor Internalization ◽  
Intensive Study ◽  
Receptor Stimulation ◽  
Surface Receptors ◽  
Regulatory Processes ◽  
Inositol 1,4,5 Trisphosphate ◽  
Cellular Responsiveness ◽  
Intracellular Second Messengers

An extensive group of cell surface receptors are coupled to phosphoinositidase C and thus to the production of the intracellular second messengers inositol 1,4,5-trisphosphate and 1,2-diacylglycerol. While the mechanisms and consequences of phosphoinositidase C activation have been the target of intensive study for over a decade, information is scarce regarding the regulatory processes that modulate this system during receptor stimulation. This situation, however, is now beginning to change. Recent data indicate (a) that Ca2+, mobilized concurrently with activation of phosphoinositidase-C-linked receptors, is a feedback activator and amplifier of phosphoinositide hydrolysis, (b) that rapid desensitization, possibly associated with receptor phosphorylation, regulates phosphoinositidase-C-linked receptors, (c) that receptor internalization can mediate desensitization at later times and (d) that signalling can be regulated at additional sites downstream of phosphoinositidase C. These diverse regulatory events provide the means by which the breakdown of phosphoinositides and cellular responsiveness to their products are controlled during cell stimulation.

scholarly journals Interleukin-3 down-regulates its own receptor

Blood ◽  
1989 ◽  
Vol 73 (5) ◽  
pp. 1180-1187
Author(s):  
SC Murthy ◽  
PH Sorensen ◽  
AL Mui ◽  
G Krystal
Keyword(s):  
Cell Surface ◽  
Calf Serum ◽  
High Density ◽  
Receptor Expression ◽  
Receptor Internalization ◽  
Cell Surface Receptor ◽  
Cell Populations ◽  
Low Density ◽  
Interleukin 3 ◽  
Receptor Number

To gain insight into the mechanisms involved in regulating murine interleukin-3 (mIL-3) receptor expression, we have examined the effects of mIL-3 and murine granulocyte-macrophage colony-stimulating factor (mGM-CSF) on mIL-3 receptor internalization and re-expression and studied the relationship between mIL-3 cell surface receptor density and growth factor sensitivity. As a source of cells for our studies, we used a B6SUtA clone, B6SUtA1, which grows equally well in mIL-3 or mGM- CSF when supplemented with 20% fetal calf serum (FCS) in RPMI 1640. Intracellular processing studies carried out in the presence and absence of methylamine suggested that mIL-3 is cleaved at two specific sites before its complete digestion within lysosomes. However, unlike its ligand, cycloheximide studies indicated that internalized mIL-3 receptors are recycled to the cell surface. When B6SUtA1 cells were continuously passaged in mIL-3, cell populations allowed to exhaust the mIL-3 in the medium (high density cells) expressed more than ten times (ie, approximately 100,000/cell) the mIL-3 receptor number of those growing exponentially at low cell concentrations (low density cells). Since the high density cells were no larger than the low density cells, the marked increase in mIL-3 receptor number per cell reflects a true up-regulation of receptor expression. A kinetic analysis of this up- regulation revealed that it begins within one hour of mIL-3 exhaustion. Moreover, proliferation assays with these two cell populations, using 3H-thymidine incorporation, suggested that the high density cells were 30-fold more responsive to mIL-3. However, when B6SUtA1 cells were passaged in mGM-CSF, there was no difference in mIL-3 receptor number between high density and low density cells (ie, approximately 100,000/cell). Identical studies carried out with another mIL-3 dependent cell line, 32D C3, demonstrated that this phenomenon was not unique to B6SUtA1 cells.

scholarly journals Interleukin-3 down-regulates its own receptor

Blood ◽  
1989 ◽  
Vol 73 (5) ◽  
pp. 1180-1187 ◽  
Author(s):  
SC Murthy ◽  
PH Sorensen ◽  
AL Mui ◽  
G Krystal
Keyword(s):  
Cell Surface ◽  
Calf Serum ◽  
High Density ◽  
Receptor Expression ◽  
Receptor Internalization ◽  
Cell Surface Receptor ◽  
Cell Populations ◽  
Low Density ◽  
Interleukin 3 ◽  
Receptor Number

Abstract To gain insight into the mechanisms involved in regulating murine interleukin-3 (mIL-3) receptor expression, we have examined the effects of mIL-3 and murine granulocyte-macrophage colony-stimulating factor (mGM-CSF) on mIL-3 receptor internalization and re-expression and studied the relationship between mIL-3 cell surface receptor density and growth factor sensitivity. As a source of cells for our studies, we used a B6SUtA clone, B6SUtA1, which grows equally well in mIL-3 or mGM- CSF when supplemented with 20% fetal calf serum (FCS) in RPMI 1640. Intracellular processing studies carried out in the presence and absence of methylamine suggested that mIL-3 is cleaved at two specific sites before its complete digestion within lysosomes. However, unlike its ligand, cycloheximide studies indicated that internalized mIL-3 receptors are recycled to the cell surface. When B6SUtA1 cells were continuously passaged in mIL-3, cell populations allowed to exhaust the mIL-3 in the medium (high density cells) expressed more than ten times (ie, approximately 100,000/cell) the mIL-3 receptor number of those growing exponentially at low cell concentrations (low density cells). Since the high density cells were no larger than the low density cells, the marked increase in mIL-3 receptor number per cell reflects a true up-regulation of receptor expression. A kinetic analysis of this up- regulation revealed that it begins within one hour of mIL-3 exhaustion. Moreover, proliferation assays with these two cell populations, using 3H-thymidine incorporation, suggested that the high density cells were 30-fold more responsive to mIL-3. However, when B6SUtA1 cells were passaged in mGM-CSF, there was no difference in mIL-3 receptor number between high density and low density cells (ie, approximately 100,000/cell). Identical studies carried out with another mIL-3 dependent cell line, 32D C3, demonstrated that this phenomenon was not unique to B6SUtA1 cells.

scholarly journals Calcitonin/Amylin Receptors and Ramps

2001 ◽  
Vol 1 ◽  
pp. 9-9
Author(s):  
Patrick M. Sexton
Keyword(s):  
Cell Surface ◽  
Protein Interactions ◽  
Receptor Expression ◽  
Cell Surface Receptor ◽  
Calcitonin Receptor ◽  
Receptor Function ◽  
Surface Receptor ◽  
Receptor Activity Modifying Proteins ◽  
G Protein Coupled ◽  
Novel Protein

Our understanding of G protein-coupled receptor function has recently expanded to encompass novel protein interactions that underlie both cell surface receptor expression and the exhibited phenotype. The most notable examples are those involving receptor activity modifying proteins (RAMPs). RAMP association with the calcitonin receptor-like receptor (CRLR) traffics this receptor to the cell surface, where individual RAMPs dictate the expression of unique phenotypes.

scholarly journals Identification of the Transferrin Receptor as a Novel Immunoglobulin (Ig)a1 Receptor and Its Enhanced Expression on Mesangial Cells in Iga Nephropathy

2001 ◽  
Vol 194 (4) ◽  
pp. 417-426 ◽  
Author(s):  
Ivan C. Moura ◽  
Miguel N. Centelles ◽  
Michelle Arcos-Fajardo ◽  
Denise M. Malheiros ◽  
James F. Collawn ◽  
...  
Keyword(s):  
Cell Surface ◽  
Iga Nephropathy ◽  
Transferrin Receptor ◽  
B Lymphocyte ◽  
Mesangial Cells ◽  
Surface Protein ◽  
Receptor Expression ◽  
Glomerular Mesangial Cells ◽  
Surface Receptors ◽  
Enhanced Expression

The biological functions of immunoglobulin (Ig)A antibodies depend primarily on their interaction with cell surface receptors. Four IgA receptors are presently characterized. The FcαRI (CD89) expressed by myeloid cells selectively binds IgA1 and IgA2 antibodies, whereas the poly-IgR, Fcα/μR, and asialoglycoprotein receptors bind other ligands in addition to IgA. IgA binding by mesangial cells, epithelial cells, and proliferating lymphocytes is also well documented, but the nature of the IgA receptors on these cells remains elusive. A monoclonal antibody (A24) is described here that specifically blocks IgA binding to epithelial and B lymphocyte cell lines. Both the A24 antibody and IgA1 myelomas bind a cell surface protein that is identified as the transferrin receptor (CD71). The transferrin receptor selectively binds IgA1 antibodies, monomeric better than polymeric forms, and the IgA1 binding is inhibitable by transferrin. Transferrin receptor expression is upregulated on cultured mesangial cells as well as on glomerular mesangial cells in patients with IgA nephropathy. The characterization of transferrin receptor as a novel IgA1 receptor on renal mesangial cells suggests its potential involvement in the pathogenesis of IgA nephropathy.

scholarly journals SPaRTAN, a computational framework for linking cell-surface receptors to transcriptional regulators

2021 ◽  
Vol 49 (17) ◽  
pp. 9633-9647
Author(s):  
Xiaojun Ma ◽  
Ashwin Somasundaram ◽  
Zengbiao Qi ◽  
Douglas J Hartman ◽  
Harinder Singh ◽  
...  
Keyword(s):  
Cell Surface ◽  
Single Cell ◽  
Transcriptional Regulators ◽  
Cell Types ◽  
Receptor Expression ◽  
Cell Surface Receptor ◽  
Cell Surface Receptors ◽  
Surface Receptors ◽  
Surface Receptor ◽  
Context Specific

Abstract The identity and functions of specialized cell types are dependent on the complex interplay between signaling and transcriptional networks. Recently single-cell technologies have been developed that enable simultaneous quantitative analysis of cell-surface receptor expression with transcriptional states. To date, these datasets have not been used to systematically develop cell-context-specific maps of the interface between signaling and transcriptional regulators orchestrating cellular identity and function. We present SPaRTAN (Single-cell Proteomic and RNA based Transcription factor Activity Network), a computational method to link cell-surface receptors to transcription factors (TFs) by exploiting cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) datasets with cis-regulatory information. SPaRTAN is applied to immune cell types in the blood to predict the coupling of signaling receptors with cell context-specific TFs. Selected predictions are validated by prior knowledge and flow cytometry analyses. SPaRTAN is then used to predict the signaling coupled TF states of tumor infiltrating CD8+ T cells in malignant peritoneal and pleural mesotheliomas. SPaRTAN enhances the utility of CITE-seq datasets to uncover TF and cell-surface receptor relationships in diverse cellular states.

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