Galectin genes: Regulation of expression

In this review we have summarized the more recent studies on the expression of mammalian galectins. One interesting observation that can be made is that in most of microarrays and/or differential display analysis performed in recent years one or more galectins have been picked up. From a critical evaluation of the pertinent studies the main conclusion that can be drawn is that, although it is not yet clear whether the 14 galectins identified so far have functions in common, a striking common feature of all galectins is the strong modulation of their expression during development, differentiation stages and under different physiological or pathological conditions. This suggests that the expression of different galectins is finely tuned and possibly coordinated. In spite of these observations it is rather unexpected that very few studies have been performed on the molecular mechanisms governing the activity of galectin genes. Published in 2004.     

Control of galectin gene expression.

In this review we summarize the available information on the expression of mammalian galectins in normal and transformed cells. From all these studies it is apparent that each cell might express most of galectins; yet, during development or in various differentiation stages or under different physiological or pathological conditions, one or more galectins are preferentially expressed in each cell type. This implies a fine control of gene expression and suggests that such control should be coordinated. Nevertheless, to date very few studies have been performed on the mechanisms responsible for the regulation of galectin genes. We review the current knowledge on galectin promoter function. We believe that this area of galectin research will expand rapidly in the near future.     

Insect galectins: roles in immunity and development

As evidenced by the reviews in this special issue of Glycoconjugate Journal, much research is focused on determining functions for mammalian galectins. However, the identification of precise functions for mammalian galectins may be complicated by redundancy in tissue expression and in target cell recognition of the many mammalian galectins. Therefore, lower organisms may be useful in deciphering precise functions for galectins. Unfortunately, some genetically manipulable model systems such as Caenorhabditis elegans may have more galectins than mammals. Recently, galectins were identified in two well-studied insect systems, Drosophila melanogaster and Anopheles gambiae. In addition to the powerful genetic manipulation available in these insect models, there is a sophisticated understanding of many biological processes in these organisms that can be directly compared and applied to mammalian systems. Understanding the roles of galectins in insects may provide insight into precise functions of galectins in mammals.     

Galectins and urological cancer

Galectins are a family of proteins defined by their affinity for beta-galactoside and by their conserved sequence. Each galectins exhibits a specific expression pattern in various tissues and their expression is regulated during development. Their expression is altered in many types of cancers and non-cancerous disorders. They interact with glycoproteins in both extracellular and intracellular milieu and regulate various biological phenomenon including cell growth, cell differentiation, cell adhesion, and apoptosis. A series of experimental and clinical evidences have been reported to support correlation between galectin expressions and neoplastic transformation. The recent findings show that expressions of galectins are elevated with neoplastic progression in certain malignancies, and therefore, galectins are expected to serve as reliable tumor markers. In this review, we describe the expression and role of galectins in urological cancers and their clinical applications for diagnostic and therapeutic use.     

Specificity of human galectins on cell surfaces

Galectins are ß-galactoside-binding proteins sharing homology in amino acid sequence of their carbohydraterecognition domain. Their carbohydrate specificity outside cells has been studied previously. The main conclusion of these studies was that several levels of glycan ligand recognition exist for galectins: (i) disaccharide Galß1-4GlcNAc (LN, Nacetyllactosamine) binds stronger than ß-galactopyranose; (ii) substitution at 0 -2 and 0 -3 of galactose residue as well as core fragments (“right” from GlcNAc) provides significant increase in affinity; (iii) similarly glycosylated proteins can differ significantly in affinity to galectins. Information about the natural cellular receptors of galectins is limited. Until recently, it was impossible to study specificity of cell-bound galectins. A model based on controlled incorporation of a single protein into glycocalyx of cells and subsequent interaction of loaded cells with synthetic glycoprobes measured by flow cytometry made this possible recently. In this review, data about glycan specificity of proto-, chimera-, and tandem-repeat type galectins on the cell surface are systematized, and comparative analysis of the results with data on specificity of galectins in artificial systems was performed. The following conclusions from these studies were made: (i) cellular galectins have practically no ability to bind disaccharide LNⁿ, but display affinity to 3'-substituted oligolactosamines and oligomers LNⁿ; (ii) tandem-repeat type galectins recognize another disaccharide, namely Galß1-3GlcNAc (Le^c); (iii) on the cell surface, tandemrepeat type galectins conserve the ability to display high affinity to blood group antigens of ABH system; (iv) in general, when galectins are immersed into glycocalyx, they are more selective regarding glycan interactions. Thus, we conclude that competitive interaction of galectins with cell microenvironment (endogenous cell glycans) is the main factor providing selectivity of galectins in vivo.     

Galectins and cancer

The galectins are a family of proteins that are distributed widely in all living organisms. All of them share galactose-specificity. At present, 14 members of the family are characterized in mammals. The galectins have been implicated in many essential functions including development, differentiation, cell-cell adhesion, cell-matrix interaction, growth regulation, apoptosis, RNA splicing, and tumor metastasis. Although efforts have mostly focused on the possible function of galectins in tumor development and invasiveness, their precise role in this field is still debated. This review discusses the recent way in which the expression of galectins and galectin-binding sites may affect the behavior of a variety of human neoplastic tissues.     

Galectins in kidney development

Galectins are a family of proteins with overlapping but distinct carbohydrate-binding specificities. They differ in cell-type and tissue distribution, and have various functions. Extracellularly several galectins can modulate cellular adhesive interactions and signalling pathways, effects that may be important in the establishment and maintenance of tissue organization during normal development. This review will summarise recent progress in defining the roles of galectins that are expressed in the kidney in normal development, and discuss the evidence linking aberrant expression of galectins with kidney disease.     

Glycosylation, galectins and cellular signaling

Glycosylation is a common posttranslational modification of proteins and lipids of the secretory pathway that generates binding sites for galactose-specific lectins or galectins. Branching of Asn-linked (N-)glycans by the N-acetylglucosaminyltransferases (Mgat genes) increases affinity for galectins. Both tissue-specific expression of the enzymes and the metabolic supply of sugar-nucleotides to the ER and Golgi regulate glycan distribution while protein sequences specify NXS/T site multiplicity, providing metabolic and genetic contributions to galectin-glycoprotein interactions. Galectins cross-link glycoproteins forming dynamic microdomains or lattices that regulate various mediators of cell adhesion, migration, proliferation, survival and differentiation. There are a similar number of galactose-specific galectins in C. elegans and humans, but expression of higher-affinity branched N-glycans are a more recent feature of vertebrate evolution. Galectins might be considered a reading code for repetition of the minimal units of binding [Gal(NAc)β1-3/4GlcNAc] and NXS/T site multiplicity in proteins. The rapidly evolving and structurally complex Golgi modifications to surface receptors are interpreted through affinity for the lattice, which regulates receptor levels as a function of the cellular environment, and thereby the probability of various cell fates. Many important questions remain concerning the regulation of the galectins, the glycan ligands and lattice interaction with other membrane domains and endocytic pathways.     

Insect galectins: Roles in immunity and development

As evidenced by the reviews in this special issue of Glycoconjugate Journal, much research is focused on determining functions for mammalian galectins. However, the identification of precise functions for mammalian galectins may be complicated by redundancy in tissue expression and in target cell recognition of the many mammalian galectins. Therefore, lower organisms may be useful in deciphering precise functions for galectins. Unfortunately, some genetically manipulable model systems such as Caenorhabditis elegans may have more galectins than mammals. Recently, galectins were identified in two well-studied insect systems, Drosophila melanogaster and Anopheles gambiae. In addition to the powerful genetic manipulation available in these insect models, there is a sophisticated understanding of many biological processes in these organisms that can be directly compared and applied to mammalian systems. Understanding the roles of galectins in insects may provide insight into precise functions of galectins in mammals. Published in 2004.     

Galectins in kidney development

Galectins are a family of proteins with overlapping but distinct carbohydrate-binding specificities. They differ in cell-type and tissue distribution, and have various functions. Extracellularly several galectins can modulate cellular adhesive interactions and signalling pathways, effects that may be important in the establishment and maintenance of tissue organization during normal development. This review will summarise recent progress in defining the roles of galectins that are expressed in the kidney in normal development, and discuss the evidence linking aberrant expression of galectins with kidney disease. Published in 2004.     

90K (Mac-2 BP) and galectins in tumor progression and metastasis

Galectins and their ligands have been implicated in cell transformation and cancer metastasis, and found to have prognostic value. Mac-2 BP, also known as 90K, is a highly glycosylated, secreted protein extensively studied in human cancer, which binds galectin-1, galectin-3 and galectin-7. High expression levels of 90K are associated with a shorter survival, the occurrence of metastasis or a reduced response to chemotherapy in patients with different types of malignancy. The mechanisms underlying the prognostic significance of 90K and galectins in cancer are far from being understood, although they may be related to the ability of these proteins to interact and, to some extent, modulate cell-cell and cell-matrix adhesion and apoptosis. The resulting scenario is even more complex, as data have been presented that all these proteins might be associated with either a positive or a negative outcome of the patients. It is hypothesised that different galectins and galectin ligands with overlapping or opposite functions, expressed in different tumors during the different steps of the metastatic cascade might play a crucial role in tumor progression. Published in 2004.     

90K (Mac-2 BP) and galectins in tumor progression and metastasis

Galectins and their ligands have been implicated in cell transformation and cancer metastasis, and found to have prognostic value. Mac-2 BP, also known as 90K, is a highly glycosylated, secreted protein extensively studied in human cancer, which binds galectin-1, galectin-3 and galectin-7. High expression levels of 90K are associated with a shorter survival, the occurrence of metastasis or a reduced response to chemotherapy in patients with different types of malignancy. The mechanisms underlying the prognostic significance of 90K and galectins in cancer are far from being understood, although they may be related to the ability of these proteins to interact and, to some extent, modulate cell-cell and cell-matrix adhesion and apoptosis. The resulting scenario is even more complex, as data have been presented that all these proteins might be associated with either a positive or a negative outcome of the patients. It is hypothesised that different galectins and galectin ligands with overlapping or opposite functions, expressed in different tumors during the different steps of the metastatic cascade might play a crucial role in tumor progression.     

Galectins as modulators of cell adhesion

The galectins are a family of carbohydrate-binding proteins that are distributed widely in metazoan organisms. Each galectin exhibits a specific pattern of expression in various cells and tissues, and expression is often closely regulated during development. Although these proteins are found mainly in the cell cytoplasm, some are secreted from cells and interact with appropriately glycosylated proteins at the cell surface or within the extracellular matrix. These receptors include cell-adhesion molecules such as integrins, and matrix glycoproteins such as laminin and fibronectin isoforms. Recent studies have increased understanding of the roles of the galectins in regulating cell-cell and cell-matrix adhesion. These interactions are critically involved in modulation of normal cellular motility and polarity and during tissue formation, and loss of adhesive function is implicated in several disease states including tumour progression, inflammation and cystic development in branching epithelia such as kidney tubules. This review discusses recent progress in defining the specificities and mechanisms of action of secreted galectins as multifunctional cell regulators.     

Galectin-4 in normal tissues and cancer

Galectin-4 belongs to a subfamily of galectins composed of two carbohydrate recognition domains within the same peptide chain. The two domains have all the conserved galectin signature amino acids, but their overall sequences are only approximately 40% identical. Both domains bind lactose with a similar affinity as other galectins, but their respective preferences for other disaccharides, and larger saccharides, are distinctly different. Thus galectin-4 has a property of a natural cross-linker, but in a modified sense since each domain prefers a different subset of ligands. Similarly to other galectins, galectin-4 is synthesized as a cytosolic protein, but can be externalized. During development and in adult normal tissues, galectin-4 is expressed only in the alimentary tract, from the tongue to the large intestine. It is often found in relatively insoluble complexes, as a component of either adherens junctions or lipid rafts in the microvillus membrane, and it has been proposed to stabilize these structures. Strong expression of galectin-4 can be induced, however, in cancers from other tissues including breast and liver. Within a collection of human epithelial cancer cell lines, galectin-4 is overexpressed and soluble in those forming highly differentiated polarized monolayers, but absent in less differentiated ones. In cultured cells, intracellular galectin-4 may promote resistance to nutrient starvation, whereas--as an extracellular protein--it can mediate cell adhesion. Because of its distinct induction in breast and other cancers, it may be a valuable diagnostic marker and target for the development of inhibitory carbohydrate-based drugs.     

Role of galectins in inflammatory and immunomodulatory processes

Galectins are members of a highly conserved family of beta-galactoside-binding animal lectins. Presently, more than 14 members have been identified and additional homologues are likely to be discovered. Given their conservation throughout animal evolution, it is not surprising that they could play key roles in innate and adaptive immune responses, through sugar-dependent and -independent mechanisms. Recently, it has become increasingly clear that galectins can differentially affect cellular activation and function. These biological effects attracted attention of researchers in cell biology, biochemistry, glycobiology and immunology, not only in the mode of action of galectins, but also in their role as putative modulators of immune surveillance, apoptosis, cell adhesion and chemotaxis. Here we will summarize the state-of-the-art of the effects of galectins in inflammatory and immunomodulatory processes. In addition, we will discuss in-depth the current knowledge about the effects of this enigmatic family of animal lectins and their glycoligands in the progression, diagnosis and treatment of different pathological processes such as autoimmunity, allergy, infection and chronic inflammation.