Showing papers on "Galectin published in 2007"
TL;DR: Computational and experimental data reveal that features allow nutrient flux stimulated by growth-promoting high-n receptors to drive arrest/differentiation programs by increasing surface levels of low-n glycoproteins.
803 citations
TL;DR: Galectins, a family of animal lectins with affinity for beta-galactosides, can form multivalent complexes with cell surface glycoconjugates and deliver a variety of intracellular signals to modulate cell activation, differentiation, and survival as mentioned in this paper.
352 citations
TL;DR: These intriguing glycan-binding proteins offer promising possibilities for the treatment and intervention of a wide variety of pathological processes, including cancer, inflammation, and autoimmunity.
Abstract: Galectins are a taxonomically widespread family of glycan-binding proteins, defined by at least one conserved carbohydrate-recognition domain with a canonical amino acid sequence and affinity for beta-galactosides Because of their anti-adhesive as well as pro-adhesive extracellular functions, galectins appear to be a novel class of adhesion-modulating proteins collectively known as matricellular proteins (which include thrombospondin, SPARC, tenascin, hevin, and disintegrins) Accordingly, galectins can display de-adhesive effects when presented as soluble proteins to cells in a strong adhesive state In this context, the de-adhesive properties of galectins should be considered as physiologically relevant as the proadhesive effects of these glycan-binding proteins This article focuses on the roles of mammalian galectins in cell adhesion, spreading, and migration, and the crossregulation of these functions Although careful attention should be paid when examining individual galectin functions due to overlapping distributions, these intriguing glycan-binding proteins offer promising possibilities for the treatment and intervention of a wide variety of pathological processes, including cancer, inflammation, and autoimmunity
331 citations
TL;DR: Caveolin-1 is a conditional tumor suppressor whose loss is advantageous when β1,6GlcNAc-branched N-glycans are below a threshold for optimal galectin lattice formation.
Abstract: Macromolecular complexes exhibit reduced diffusion in biological membranes; however, the physiological consequences of this characteristic of plasma membrane domain organization remain elusive. We report that competition between the galectin lattice and oligomerized caveolin-1 microdomains for epidermal growth factor (EGF) receptor (EGFR) recruitment regulates EGFR signaling in tumor cells. In mammary tumor cells deficient for Golgi β1,6N-acetylglucosaminyltransferase V (Mgat5), a reduction in EGFR binding to the galectin lattice allows an increased association with stable caveolin-1 cell surface microdomains that suppresses EGFR signaling. Depletion of caveolin-1 enhances EGFR diffusion, responsiveness to EGF, and relieves Mgat5 deficiency–imposed restrictions on tumor cell growth. In Mgat5+/+ tumor cells, EGFR association with the galectin lattice reduces first-order EGFR diffusion rates and promotes receptor interaction with the actin cytoskeleton. Importantly, EGFR association with the lattice opposes sequestration by caveolin-1, overriding its negative regulation of EGFR diffusion and signaling. Therefore, caveolin-1 is a conditional tumor suppressor whose loss is advantageous when β1,6GlcNAc-branched N-glycans are below a threshold for optimal galectin lattice formation.
248 citations
TL;DR: A body of knowledge, documenting the coming of age of galectins as potential immunosuppressive agents or targets for anti‐inflammatory drugs, represents a sound basis to further explore their potential as novel therapies for autoimmune diseases, chronic inflammation and cancer.
Abstract: Inflammation is a critical process for eliminating pathogens, but can lead to serious deleterious effects if left unchecked Identifying the endogenous factors that control immune tolerance and inflammation is a key goal in the field of immunology Galectins, a family of endogenous lectins with affinity for beta-galactoside-containing oligosaccharides, are expressed by several cells of the immune system and tissue-resident stromal cells According to their architecture, this family of glycan-binding proteins is classified in those containing one-carbohydrate-recognition domain (CRD) (proto-type), those containing two-CRD joined by a linker non-lectin domain (tandem-repeat) and those that have one-CRD attached to an N-terminal peptide (chimera-type) Accumulating evidence indicates that galectins play critical regulatory roles in immune cell response and homeostasis In this review, we summarize recent developments in our understanding of the galectins' roles within different immune cell compartments, and in the broader context of the inflammatory microenvironments In particular we illustrate the immunoregulatory role of three representative members of each galectin subfamily: galectin-1, -3 and -9 This body of knowledge, documenting the coming of age of galectins as potential immunosuppressive agents or targets for anti-inflammatory drugs, represents a sound basis to further explore their potential as novel therapies for autoimmune diseases, chronic inflammation and cancer
239 citations
TL;DR: Data suggest that galectin-3 lattices are robust and could, thus, be involved, as previously proposed, in the restriction of receptor clustering, and lattice formation.
215 citations
TL;DR: In this paper, a member of the lectin family, called galectin-10, was identified as constitutively expressed in human CD25+ Treg cells, while they are nearly absent in resting and activated CD4+ T cells.
195 citations
TL;DR: It is suggested that the interplay between multiple Tim-3-binding activities contributes to the regulated assembly of signaling complexes required for effective Th1-mediated immunity.
193 citations
TL;DR: This review focuses on the recent progress in understanding of the regulation and functional significance of increased TF occurrence in cancer progression and metastasis.
Abstract: The oncofetal Thomsen–Friedenreich carbohydrate antigen (Galβ1-3GalNAcα1-Ser/Thr TF or T antigen) is a pan-carcinoma antigen highly expressed by about 90% of all human carcinomas. Its broad expression and high specificity in cancer have attracted many investigations into its potential use in cancer diagnosis and immunotherapy. Over the past few years increasing evidence suggests that the increased TF occurrence in cancer cells may be functionally important in cancer progression by allowing increased interaction/communication of the cells with endogenous carbohydrate-binding proteins (lectins), particularly the members of the galactoside-binding galectin family. This review focuses on the recent progress in understanding of the regulation and functional significance of increased TF occurrence in cancer progression and metastasis.
179 citations
TL;DR: Galectin-8 binding and signaling at cell surfaces can be explained by combined binding of the two CRDs to low or medium affinity ligand, and their highest affinity ligands, such as sialylated galactosides, are not required.
Abstract: Galectin-8 has two different carbohydrate recognition domains (CRDs), the N-terminal Gal-8N and the C-terminal Gal-8C linked by a peptide, and has various effects on cell adhesion and signaling. To understand the mechanism for these effects further, we compared the binding activities of galectin-8 in solution with its binding and activation of cells. We used glycan array analysis to broaden the specificity profile of the two galectin-8 CRDs, as well as intact galectin-8s (short and long linker), confirming the unique preference for sulfated and sialylated glycans of Gal-8N. Using a fluorescence anisotropy assay, we examined the solution affinities for a subset of these glycans, the highest being 50 nM for NeuAc alpha 2,3Lac by Gal-8N. Thus, carbohydrate-protein interactions can be of high affinity without requiring multivalency. More importantly, using fluorescence polarization, we also gained information on how the affinity is built by multiple weak interactions between different fragments of the glycan and its carrier molecule and the galectin CRD subsites (A-E). In intact galectin-8 proteins, the two domains act independently of each other in solution, whereas at a surface they act together. Ligands with moderate or weak affinity for the isolated CRI)s on the array are bound strongly by intact galectin-8s. Also galectin-8 binding and signaling at cell surfaces can be explained by combined binding of the two CRI)s to low or medium affinity ligands, and their highest affinity ligands, such as sialylated galactosides, are not required. (Less)
174 citations
TL;DR: It is concluded that p16INK4a orchestrates distinct aspects of glycosylation that are relevant for integrin maturation and reactivity to an endogenous effector as well as the effector's expression.
Abstract: Expression of the tumor suppressor p16(INK4a) after stable transfection can restore the susceptibility of epithelial tumor cells to anoikis. This property is linked to increases in the expression and cell-surface presence of the fibronectin receptor. Considering its glycan chains as pivotal signals, we assumed an effect of p16(INK4a) on glycosylation. To test this hypothesis for human Capan-1 pancreatic carcinoma cells, we combined microarray for selected glycosyltransferase genes with 2D chromatographic glycan profiling and plant lectin binding. Major differences between p16-positive and control cells were detected. They concerned expression of beta1,4-galactosyltransferases (down-regulation of beta1,4-galactosyltransferases-I/V and up-regulation of beta1,4-galactosyltransferase-IV) as well as decreased alpha2,3-sialylation of O-glycans and alpha2,6-sialylation of N-glycans. The changes are compatible with increased beta(1)-integrin maturation, subunit assembly and binding activity of the alpha(5)beta(1)-integrin. Of further functional relevance in line with our hypothesis, we revealed differential reactivity towards endogenous lectins, especially galectin-1. As a result of reduced sialylation, the cells' capacity to bind galectin-1 was enhanced. In parallel, the level of transcription of the galectin-1 gene increased conspicuously in p16(INK4a)-positive cells, and even figured prominently in a microarray on 1996 tumor-associated genes and in proteomic analysis. The cells therefore gain optimal responsiveness. The correlation between genetically modulated galectin-1 levels and anoikis rates in engineered transfectants inferred functional significance. To connect these findings to the fibronectin receptor, galectin-1 was shown to be co-immunoprecipitated. We conclude that p16(INK4a) orchestrates distinct aspects of glycosylation that are relevant for integrin maturation and reactivity to an endogenous effector as well as the effector's expression. This mechanism establishes a new aspect of p16(INK4a) functionality.
TL;DR: Gal-9 reduced AHR as well as Th2-associated airway inflammation and inhibited interactions with hyaluronan in mice tested, consistent with the concept that CD44–HA interactions mediate the migration of T cells into the lung.
Abstract: Rationale: Galectin-9 (Gal-9) belongs to the galectin family, which exhibits affinity for β-galactosides. Gal-9 has a variety of biological activities; however, its role in allergic inflammation is unknown.Objectives: We evaluated the effect of a stable form of the human protein on allergic airway inflammation in a mite allergen–induced asthma model.Methods: Human stable Gal-9 was given by intravenous injection to mice during antigen challenge. The effect of Gal-9 on airway inflammation and airway hyperresponsiveness (AHR) was then evaluated.Measurements and Main Results: Gal-9 reduced AHR as well as Th2-associated airway inflammation. Furthermore, administration of Gal-9 as well as anti-CD44 monoclonal antibody inhibited the infiltration of peripheral blood Th2 cells into the airway. Interestingly, Gal-9 directly bound the CD44 adhesion molecule and inhibited interactions with hyaluronan (HA). Consistent with the concept that CD44–HA interactions mediate the migration of T cells into the lung, Gal-9 bloc...
TL;DR: Novel immunoregulatory contribution of galectins in regulating leukocyte turnover independently of apoptosis is suggested, indicating that galectin's effects are cell specific.
TL;DR: The role of galectin-3 is described as an anti-apoptotic factor in response to chemotherapeutic drugs and recent data on its molecular mechanism that contribute to drug resistance are discussed.
TL;DR: This review focuses on the expression of galectins in the tumor endothelium, their contribution to tumor progression, and their application in tumor-type independent cancer therapy.
TL;DR: Glycosylation changes during DC maturation were corroborated by mass spectrometric analysis of N- and O-glycans and by flow cytometry using plant lectins and glycan-specific Abs.
Abstract: Dendritic cells (DC) are the most potent APC in the organism. Immature dendritic cells (iDC) reside in the tissue where they capture pathogens whereas mature dendritic cells (mDC) are able to activate T cells in the lymph node. This dramatic functional change is mediated by an important genetic reprogramming. Glycosylation is the most common form of posttranslational modification of proteins and has been implicated in multiple aspects of the immune response. To investigate the involvement of glycosylation in the changes that occur during DC maturation, we have studied the differences in the glycan profile of iDC and mDC as well as their glycosylation machinery. For information relating to glycan biosynthesis, gene expression profiles of human monocyte-derived iDC and mDC were compared using a gene microarray and quantitative real-time PCR. This gene expression profiling showed a profound maturation-induced up-regulation of the glycosyltransferases involved in the expression of LacNAc, core 1 and sialylated structures and a down-regulation of genes involved in the synthesis of core 2 O-glycans. Glycosylation changes during DC maturation were corroborated by mass spectrometric analysis of N- and O-glycans and by flow cytometry using plant lectins and glycan-specific Abs. Interestingly, the binding of the LacNAc-specific lectins galectin-3 and -8 increased during maturation and up-regulation of sialic acid expression by mDC correlated with an increased binding of siglec-1, -2, and -7.
TL;DR: The counterbalancing activities of the galectin lattice and actin cytoskeleton negatively and positively regulate Lck activity in resting cells and CD45 versus TCR clustering and signaling at the early immune synapse, respectively.
TL;DR: Hypomorphic Golgi processing is identified as an inherited trait that determines susceptibility to EAE, provides a unique spontaneous model of MS, and suggests GlcNAc-branching deficiency may promote T cell-mediated demyelination and neurodegeneration in MS.
TL;DR: The results obtained by a combined strategy further support the concept of viewing N-glycan core substitutions as non-random additions which exert a modulatory role on ligand properties.
Abstract: Core fucosylation and the bisecting N-acetylglucosamine residue are prominent natural substitutions of the N-glycan core. To address the issue of whether these two substituents can modulate ligand properties of complex-type biantennary N-glycans, we performed chemoenzymatic synthesis of the respective galactosylated and α2,3/6-sialylated N-glycans. Neoglycoproteins were then produced to determine these glycans' reactivities with sugar receptors in solid-phase assays and with tumor cells in vitro as well as their in vivo biodistribution profiles in mice. Slight protein-type-dependent changes were noted in lectin binding, including adhesion/growth-regulatory galectins as study objects, when the data were related to properties of N-glycans without or with only one core substituent. Monitoring binding in vitro revealed cell-type-dependent changes. They delimited the ligand activity of this glycan type from that of chains with un- and monosubstituted cores. A markedly prolonged serum half-life was conferred to...
TL;DR: Structural features that provide insight in attainment of substrate specificity exhibited by porcine strains as compared to rhesus rotavirus are identified and are suggestive of a new region for interaction with cell-surface carbohydrates.
TL;DR: The aim was to analyse comprehensively the presence of galectins in urothelial tumours and to demonstrate the importance of lectins in malignancy‐associated processes.
Abstract: Aims: Lectins, and especially galectins, appear to be important in malignancy-associated processes. The aim was to analyse comprehensively the presence of galectins in urothelial tumours.
Methods and results: Non-cross-reactive antibodies against seven family members from the three subgroups (prototype: galectin-1, -2 and -7; chimera type: galectin-3; tandem-repeat type: galectin-4, -8 and -9) were used. Gene expression was monitored in specimens of normal urothelium, fresh tumour tissue and cell lines by real-time polymerase chain reaction (PCR). The presence and evidence of tumour-associated up-regulation were shown for galectin-1 and -3. This was less clear-cut for galectin-4 and -8. Galectin-7 was expressed in all cell lines; galectin-2 and -9 were detected at comparatively low levels. Galectin-2, -3 and -8 up-regulation was observed in superficial tumours, but not in muscle-invasive tumours (P < 0.05). Immunoreactivity correlated with tumour grading for galectin-1, -2 and -8, and disease-dependent mortality correlated with galectin-2 and -8 expression. Binding sites were visualized using labelled galectins.
Conclusions: The results demonstrate a complex expression pattern of the galectin network in urothelial carcinomas. Galectin-1, -2, -3 and -8 are both potential disease markers and also possible targets for bladder cancer therapy.
TL;DR: It is found that both galectin-3 and -9 were required for optimal long term cell adhesion to both collagen I and laminin-111, and this findings emphasize the complex regulation of epithelial cell functions by galectins.
TL;DR: This review will concentrate on the immunoregulatory roles of galectins and collectins to illustrate the ability of endogenous glycan-binding proteins to act as cytokines, chemokines or growth factors, and thereby modulating innate and adaptive immune responses under physiological or pathological conditions.
TL;DR: This is the first report indicating that gal3 expression is regulated by promoter methylation in LNCaP cells and prostate tumors, and the methylation of gal3 promoter may constitute a powerful tool for early diagnosis of prostate cancer.
TL;DR: The hypothesis that LGALS15 is uniquely expressed in Caprinae endometria and functions as an attachment factor important for peri-implantation blastocyst elongation is supported.
Abstract: Galectins are a family of secreted animal lectins with biological roles in cell adhesion and migration In sheep, galectin 15 (LGALS15) is expressed specifically in the endometrial luminal (LE) and superficial glandular (sGE) epithelia of the uterus in concert with blastocyst elongation during the peri-implantation period The present study examined LGALS15 expression in the uterus of cattle, goats, and pigs Although the bovine genome contains an LGALS15-like gene, expressed sequence tags encoding LGALS15 mRNA were found only for sheep, and full-length LGALS15 cDNAs were cloned only from endometrial total RNA isolated from pregnant sheep and goats, but not pregnant cattle or pigs Ovine and caprine LGALS15 were highly homologous at the mRNA (95%) and protein (91%) levels, and all contained a conserved carbohydrate recognition domain and RGD recognition sequence for integrin binding Endometrial LGALS15 mRNA levels increased after Day 11 of both the estrous cycle and pregnancy, and were considerably increased after Day 15 of pregnancy in goats In situ hybridization detected abundant LGALS15 mRNA in endometrial LE and sGE of early pregnant goats, but not in cattle or pigs Immunoreactive LGALS15 protein was present in endometrial epithelia and conceptus trophectoderm of goat uteri and detected within intracellular crystal structures in trophectoderm and LE Recombinant ovine and caprine LGALS15 proteins elicited a dose-dependent increase in ovine trophectoderm cell attachment in vitro that was comparable to bovine fibronectin These results support the hypothesis that LGALS15 is uniquely expressed in Caprinae endometria and functions as an attachment factor important for peri-implantation blastocyst elongation
TL;DR: The library approach is defined as a facile route for the discovery of selective (glyco)peptide-based galectin inhibitors and inhibitory activity on carbohydrate-dependent galECTin binding was tested by solid-phase and cell assays.
TL;DR: The results provide a basis for the design of lectin inhibitors and drugs that exploit interactions with arginine side‐chains via aromatic moieties, which are involved in intramolecular protein salt bridges.
Abstract: Aromatic lactose 2-O-esters were synthesized and used to probe arene-arginine interactions with the galectin family of proteins. They were found to be low mu m inhibitors of galectin-1, -3, and -9N-terminal domain and moderate inhibitors of galectin-7, but not inhibitors of galectin-8N-terminal, which locks an arginine residue close to the critical, esterified lactose 2-O-position. Molecular modeling of galectins in complex with aromatic lactose 2-O-esters, as well as binding studies with a galectin-3 R186S mutant, confirmed that the inhibitory efficiency of the lactose 2-O-esters was due to the formation of strong interactions between the aromatic ester moieties and the arginine guanidinium groups of galectin-1 and -3. An important common feature shared by galectin-1 and -3 was that the arginines formed in-plane ion pairs with two side-chain carboxylates, which resulted in extended planar pi-electron surfaces that did not require solvation by water; these surfaces were ideal for stocking with aromatic moieties of the ligands. The results provide a basis for the design of lectin inhibitors and drugs that exploit interactions with arginine side-chains via aromatic moieties, which are involved in intramolecular protein salt bridges. (Less)
TL;DR: It is concluded that Gal-9 inhibits allergic inflammation of the airway and AHR by modulating CD44-dependent leukocyte recognition of the extracellular matrix.
TL;DR: This study identifies activity differences and provides information on their relation to structural divergence, epitomizing the value of this combined approach beyond galectins.
Abstract: Gene duplication and sequence divergence are driving forces toward establishing protein families. To examine how sequence changes affect carbohydrate specificity, the two closely related proto-type chicken galectins CG-14 and CG-16 were selected as models. Binding properties were analyzed using a highly sensitive solid-phase assay. We tested 56 free saccharides and 34 well-defined glycoproteins. The two galectins share preference for the II (Galβ1-4GlcNAc) versus I (Galβ1-3GlcNAc) version of β-galactosides. A pronounced difference is found owing to the reactivity of CG-14 with histo-blood group ABH active oligosaccharides and A/B active glycoproteins. These experimental results prompted to determine activity-structure correlations by modeling. Computational analysis included consideration of the flexibility of binding partners and the presence of water molecules. It provided a comparative description of complete carbohydrate recognition domains, which had so far not been characterized in animal galectins. The structural models assigned II, I selectivity to a region downstream of the central Trp moiety. Docking revealed that the tetrasaccharides can be accommodated in their free-state low-energy conformations. CG-14's preference for A versus B epitopes could be attributed to a contact between His124 and the N-acetyl group of GalNAc. Regarding intergalectin comparison, the Ala53/Cys51 exchange affects the interaction potential of His54/His52. Close inspection of simulated dynamic interplay revealed reorientation of His124 at the site of the His124/Glu123 substitution, with potential impact on ligand dissociation. In summary, this study identifies activity differences and provides information on their relation to structural divergence, epitomizing the value of this combined approach beyond galectins.
Journal Article•
TL;DR: The reduction of galectin-3 expression is associated with the invasion and metastasis of colorectal cancer.
Abstract: Background: Galectin-3, a ‚-galactoside-binding protein, has been associated with various biological processes, such as cell adhesion, recognition, proliferation, differentiation and apoptosis. The aim of this study was to determine the relationship of galectin-3 expression to clinicopathological findings in patients with colorectal cancer. Furthermore, the correlation between the expression of galectin-3 and ‚-catenin, and the Ki-67 labeling index were investigated. Materials and Methods: Immunohistochemical assessment of galectin-3, ‚-catenin and Ki-67 expression was performed on samples from 108 patients with colorectal cancer. The expression of galectin-3 was classified at the tumor surface and the invasive front, and its relationship with clinicopathological factors was considered from a statistical viewpoint. Results: There was significant liver metastasis when the expression of galectin-3 was lower at the invasive front of a tumor compared to its surface (p=0.04). There were also significant correlations between ‚-catenin expression at the tumor surface and liver metastasis and tumor stage (p=0.03, p=0.04 respectively). Conclusion: The reduction of galectin-3 expression is associated with the invasion and metastasis of colorectal cancer. A possible involvement of galectin-3 expression in tumor invasion, metastasis and proliferation in patients with colorectal cancer is suggested. The galectins are a family of carbohydrate-binding proteins characterized by domains and their affinity for ‚-galactoside- containing glycoconjugates. An important member of this family, galectin-3 is broadly expressed in normal and neoplastic cells and has been implicated in diverse biological functions including cell growth, differentiation, apoptosis, adhesion, malignant transformation and RNA processing (1, 2). ‚-Catenin plays critical roles in both intercellular adhesion and the Wnt signaling pathway (3). Wnt signaling can stabilize ‚-catenin and cause it to accumulate in the cytoplasm and nucleus, where it can act as a transcription coactivator by associating with the TCL/LEF family of transcription factors (4). Recent studies have revealed that alterations in the Wnt signaling pathway, including those resulting from mutations in APC, ‚-catenin, and axin, play important roles in the carcinogenesis of various types of malignant tumors (3, 5). Recent findings have shown that the expression of galectin-3 is uniformly elevated with neoplastic progression in certain malignancies. Several studies have shown the potential diagnostic implication of galectin-3 expression in malignancies including thyroid (6-8), pulmonary (9), gastric (10) and colon cancer (11-13), and anaplastic large-cell lymphoma (14). Meanwhile, several studies have shown that decreased expression of galectin-3 is associated with malignancies including breast (15), cervical (16), melanoma (17) and colorectal cancer (18). This suggests that inconsistent and varying amounts of galectin-3 expression in tumors of the same origin reflect the heterogenicity of tumor cells; therefore, the existence of a correlation between galectin-3 and the malignancy is unlikely. In this study, we considered the relationship between the expression of galectin-3 and ‚-catenin in colorectal cancer, and clinicopathological factors using immunohistochemical analysis. Ki-67 is a useful marker for evaluating the proliferative potential of normal and tumor cells; therefore, we studied the correlation between galectin-3 expression and the Ki-67 labeling index (19-22).