Extracellular functions of galectin-3 (1)
The biological activities of galectin-3 in the extracellular compartment mainly involve its interactions with various beta galactoside containing glycans via its carbohydrate recognition domain (CRD). The affinities of various oligosaccharides relative to lactose (Lac) for galectin-3.
The exchange of a hydroxyl group in Lac for a more hydrophobic acetamide group to make N-acetyllactosamine (LacNAc) increases affinity for galectin-3 by over six fold.
Laminin which is a key member of ECM proteins and a target for galectin-3 is a heterotrimer to which galectin-3 has a high affinity, interacting mainly with polylactosamine residues in the glycoprotein. The cleavage of galectin-3 by matrix metalloproteinases results in a fragment (∼22 kDa), which has ∼1.2–2 fold higher affinity for laminin than the full length galectin-3 and postulated that this fragment has the potential to play major physiological role(s) in the extracellular compartment. Galectin-3 at low extracellular doses can trigger superoxide production and enhance the lipopolysaccharide-induced release of interleukin-1. Colon cancer cells produce significant quantities of mucins on their surfaces and in the extracellular matrices. These mucins contain polylactosamine chains and have been demonstrated to be a major ligand for the endogenous galectin-3.
Galectin-3 in the extracellular compartment could be internalized by tumor cells just as rapidly as its exocytosis depending on its extracellular concentration. The regulation of the adhesion of tumor cells to ECM proteins by galectin-3 is largely a function of its extracellular concentration. At low to moderate in vivo extracellular concentrations (0.1–0.25 μM) of galectin-3, normal adhesion of tumor cells to ECM is achieved. At these levels, galectin-3 may even stimulate adhesion of cells to the ECM components either directly or indirectly by clustering the integrin molecules in discrete membrane microdomains thereby increasing avidity of binding. High concentration of galectin-3 can be achieved in vivo but it is possible that in certain microdomains on the cell surface, galectin-3 concentration can be high enough as to negate the interaction of integrins with their ECM ligands. When galectin-3 is added to the cells which are already adhered to the ECM proteins, the inhibition of adhesion is not as dramatic. The integrins are already engaged to their ECM ligands and the added galectin-3 may only reduce their affinities for the ECM without stimulating their endocytic uptake from the cell surface.
Galectin-3 is therefore postulated to modulate the adhesion of all cell types whose integrins are appropriately glycosylated to the ECM. In normal epithelial cells, galectin-3 is likely to play a major role in the maintenance of the differentiated phenotype rather than the interaction of cells with ECM proteins. galectin-3 like galectin-8 can be considered to function as a matricellular protein which can be both pro- and anti-adhesive. Galectin-3 may accelerate the se- cretion and expression of integrins on the cell surface and secretion/exocytosis of collagen to the extracellular compartment to enhance adhesion and spreading. Galectin-3 can bind to lipopolysaccha- rides on bacteria to mediate their interaction with host cells and extracellular matrices.