Intracellular functions of galectins

Abstract

Many galectin family members are detected primarily intracellularly in most of the systems studied, although certain members can be found both inside and outside of cells. Specific functions that are consistent with their intracellular localization have now been documented for some of the galectins. Galectin-1 and -3 have been identified as redundant pre-mRNA splicing factors. Galectin-3, -7, and -12 have been shown to regulate cell growth and apoptosis, being either anti-apoptotic or pro-apoptotic. Galectin-3 and -12 have been shown to regulate the cell cycle. In some cases, the mechanisms by which galectins exert their functions have been partially delineated in relation to known intracellular pathways associated with these processes. In addition, a number of intracellular proteins involved in these processes have been identified as the interacting ligands of certain galectins. This review summarizes the intracellular activities displayed by several galectins and discusses the possible underlying mechanisms.

Introduction

The galectin family of carbohydrate-binding proteins was initially defined on the basis of structural analysis and binding specificity studies. Membership in this family required fulfillment of two key criteria: (a) binding affinity for β-galactosides; and (b) conserved sequence elements in the carbohydrate-binding site [1]. To date, 14 mammalian galectins have been identified and numbered sequentially according to the accepted numbers for their genes in the Genome Data Base. Galectins have also been identified in many nonmammalian species, including birds, amphibians, fish, worms, sponges and fungi [2]. Screening the databases of genomic DNA sequences and expressed sequence tags has revealed additional candidates for membership in the mammalian galectin family, as well as putative galectins in plants and viruses [3]. [See related articles in this issue on Galectinomics by Cooper [4] and on How Galectins Have Evolved Oligosaccharide Specificity by Hirabayashi et al. [5]].

Each member of the galectin family contains at least one domain of about 130 amino acids, which is responsible for the observed carbohydrate-binding activity, and therefore is designated the Carbohydrate Recognition Domain (CRD) [see related article in this issue by Gabius et al. [6]]. Comparison of the amino acid sequences of the galectin polypeptides suggests a classification into subfamilies, based on the content and organization of the domains: (a) the Prototype group (galectin-1, -2, -5, -7, -10, -11, -13, and -14) contains one domain, the CRD; (b) the Tandem Repeat group (galectin-4, -6, -8, -9, and -12) contains two CRDs; and (c) the Chimera group (galectin-3) contains an unusual proline- and glycine-rich domain (also about 130 amino acids) fused onto the CRD [see related articles in this issue by Cooper [4] and Hirabayashi et al. [5]].

The three-dimensional structures of the CRDs derived from galectin-1, -2, -3, -7 and -10 have been elucidated by X-ray crystallography. These studies revealed that the CRD is folded tightly, with two anti-parallel β-pleated sheets forming a sandwich-like structure [7]. Amino acid side chains on one of these sheets form the core carbohydrate-binding site [see related article in this issue on Principle of Structures of Animal and Plant Lectins by Loris [8]]. The interaction between a galectin CRD and the monosaccharide ligand galactose is weak, with a dissociation constant in the micromolar range. For most galectins tested, the disaccharide lactose binds with about 100-fold higher affinity than galactose alone [9]. Some larger oligosaccharides exhibit even higher affinity than lactose, suggesting that the carbohydrate-binding site extends beyond the core binding site for galactose. The amino acid residues forming this extended binding site are much less conserved among the galectins than those of the core binding site and different galectins show different affinity and specificity for longer oligosaccharides. [See related articles in this issue on Binding and Cross-linking Properties of Galectins by Brewer and Dam [10]].

Studies on the expression of galectins highlight three important facts: (a) any given organism usually expresses multiple members of the galectin family; (b) different cells within an organism usually contain a different complement of galectins; and (c) almost all cells have at least one galectin. Studies on galectin-1 and -3 during mouse embryonic development suggest that each individual galectin is expressed in some tissue-specific or developmentally regulated fashion [11]. In the adult murine system, galectin-1 is abundant in a variety of cells and tissues, particularly those of mesodermal origin. Galectin-3 is found in various epithelial cells and cartilage, as well as inflammatory cells such as macrophages. On the other hand, galectin-4 expression appears to be restricted to epithelial cells of the gastrointestinal tract, while galectin-7 is confined to stratified epithelia such as the epidermis [2].

In addition to binding galactose-containing glycoconjugates, some members of the galectin family share another property in terms of their cell biology. They exhibit dual localization, being found in both the intracellular (cytoplasm and, in some cases, the nucleus) as well as the extracellular (cell surface and medium) compartments [12]. The mechanism of externalization appears to be unusual because none of the galectins contains an obvious signal sequence for directing the polypeptide into the classical endomembrane pathway for secretion. On the other hand, many of the galectins are predominantly intracellular proteins. It is the purpose of the present article to review their intracellular activities (see Table 1).