Nuclear transport of galectin-3 and its therapeutic implications

Abstract

Galectin-3, a member of β-galactoside-binding gene family is a multi-functional protein, which regulates pleiotropic biological functions such as cell growth, cell adhesion, cell-cell interactions, apoptosis, angiogenesis and mRNA processing. Its unique structure enables it to interact with a plethora of ligands in a carbohydrate dependent or independent manner. Galectin-3 is mainly a cytosolic protein, but can easily traverse the intracellular and plasma membranes to translocate into the nucleus, mitochondria or get externalized. Depending on the cell type, specific experimental conditions in vitro, cancer type and stage, galectin-3 has been reported to be exclusively cytoplasmic, predominantly nuclear or distributed between the two compartments. In this review we have summarized the dynamics of galectin-3 shuttling between the nucleus and the cytoplasm, the nuclear transport mechanisms of galectin-3, how its specific interactions with the members of β-catenin signaling pathways affect tumor progression, and its implications as a therapeutic target.

Keywords: Beta catenin; Galectin-3; Nuclear cytoplasmic transport.

Figure 1

Nuclear pore complex (NPC) structure and nucleoporins. In the box, schematic representation of the main structural components of NPC (left) and subcomplexes of nucleoprins within NPC (right) are shown. NPC essentially consists of cytoplasmic filaments, a central framework and a nuclear basket. Nucleoporins can be subdivided into different subcomplexes; Nup214 complex (Nup214, Nup88), Nup107-160 complex (Nup160, Nup133, Nup107, Nup96, Nup75, Nup43, Nup37, Sec13, Seh1), Nup62 complex (Nup62, Nup58, Nup54, Nup45), Nup93-205 complex (Nup205, Nup188, Nup155, Nup93, Nup35) and Nup98 complex (Nup98, Rae1).

Figure 2

Nucleocytoplasmic transport pathways through NPC. Karyopherin functions in nuclear import (importins) or nuclear export (exportins) are shown. Left: Importin-α recognizes and binds nuclear localization signal (NLS)-containing cargos. The importin-α forms a heterodimer with importin-β. The import complex docks at the NPC, and mediates import of cargos through NPC. In the nucleus the import complex encounters RanGTP, is disassembled and releases the cargos. Right: Exportin also recognizes and binds nuclear export signal (NES)-containing cargos in the nucleus in the presence of RanGTP. The export complex docks at the NPC, translocates to the cytoplasm and releases the cargos. Imp-α: importin-α; Imp-ß: importin-ß; Exp: exportin.

Figure 3

Schematic diagram of galectin-3 nucleocytoplasmic transport pathways. Galectin-3 is possibly translocated between nucleus and cytoplasm by both passive diffusion and active transport. During active nuclear transport, galectin-3 NLS binds to importin-α, followed by binding to importin-ß in the cytoplasm. The galectin-3–importin-α/ß complex docks at nucleoporins and enters the nucleus. The complex dissociates in the nucleus, releasing the galectin-3. In active transport into the cytoplasm, Nup98 plays an essential role in the galectin-3 export, with nuclear export protein CRM1 (exportin 1). Phosphorylation of galectin-3 by casein kinase 1 is required for the export. Gal-3: galectin-3; CK1: casein kinase 1.