Post-translational modification of galectin-3 and its role in biological function

The chimeric lectin galectin-3 is subject to structural modifications, primarily in its non-lectin domains, by phosphorylation and proteolysis. These modifications in galectin-3 structure have the potential to alter important biologic functions of intracellular and extracellular galectin-3. We have studied the effect of galectin-3 on the susceptibility of breast and colon cancer cells to death receptor-mediated apoptosis induced by TRAIL. Phosphorylation of intracellular galectin-3 can shift ligand binding from a lectin-carbohydrate to a protein-protein mode, with diverse cellular effects. Phospho-galectin-3 leads to TRAIL sensitivity by human breast cancer cells through induction of PTEN expression. In contrast, extracellular galectin-3 can lead TRAIL resistance in colon cancer cells by inhibiting the TRAIL-dependent clustering and endocytosis of death receptors. The gene for galectin-3, LGALS3 is polymorphic in human populations, and a P64H mutation has been linked to cancer incidence, TRAIL sensitivity, and the susceptibility of the galectin-3 protein to proteolytic cleavage. It is postulated that the truncated protein, which lacks the ability to dimerize, could compete with extracellular full-length galectin-3 act as a dominant-negative inhibitor.