Galectin-3 interacts with components of the nuclear ribonucleoprotein complex
The galectins are a family of small soluble sugar binding proteins characterized by a carbohydrate recognition domain (CRD). This CRD shows a conserved sequence motif and has a high affinity for ?-galactosides [1]. The family comprises 15 mammalian galectins with one or two CRDs. Part of the lectin family is distributed in many different cell types (galectin-1, galectin-3, galectin-8, galectin-9), while galectin-2, galectin-4 and galectin-7 show a more restricted distribution. According to their domain composition, galectins have been classified into three subgroups, the prototype, the tandem repeat and the chimeric type. Prototype and chimeric type galectins contain one single CRD, whereas tandem repeat galectins are composed of two CRDs. Galectin-3 is the sole chimeric type galectin. It is composed of a proline- and glycin-rich amino-terminal domain fused to a carboxy-terminal CRD. Galectin-3 can be detected intracellularly in transport vesicles, the cytoplasm and the nucleus as well as in the extracellular milieu [2, 3]. The subcellular distribution of galectin-3 depends on the cell type and the proliferation stage [4–6]. This protein is involved in a large number of physiological and pathological processes such as cell proliferation, differentiation, survival, apoptosis, intracellular trafficking and tumor progression [7, 8]. Galectin-3 expression changes with tumor category. In cancers of the thyroid, liver, stomach, and central nervous system the protein is upregulated, whereas in cancers of the breast, ovary, uterus and prostate galectin-3 is downregulated (reviewed in [9]). Moreover, the subcellular distribution of galectin-3 varies among different tumor types. In tongue carcinoma cells galectin-3 is translocated from the nucleus to the cytoplasm during neoplastic progression [10]. In human colon and prostate carcinoma cells galectin-3 is generally down-regulated and consistently excluded from the nucleus [11]. On the other hand, in esophageal squamous cell carcinoma patients elevated expression of galectin-3 in the nucleus is a significant pathological parameter related to histological differentiation and vascular invasion [12].
Nuclear galectin-3 has a wide range of functions, one of them is the regulation of gene transcription. Galectin-3 promotes trans-activation functions of transcription factors CREB and Sp1, and induces cyclin D1 promoter activity in human breast epithelial cells [13]. Galectin-3 also modulates gene transcription by the interaction with the nuclear thyroid-specific transcription factor TTF-1 [14]. As transcriptional co-regulator, galectin-3 also binds Suppressor of fused, a negative regulator of the hedgehog signal-transduction pathway shuttling between the cytoplasm and the nucleus [15]. Another role of nuclear galectin-3 is its function as a pre-mRNA splicing factor. Early experiments already revealed that galectin-3 interacts with components of the nuclear ribonucleoprotein complex (hnRNP) [16]. Thereafter, a requirement for galectin-3 in pre-mRNA splicing was reported [17].
In our previous studies we observed an increase in nuclear translocation of galectin-3 in clear cell renal cell carcinoma cells [18]. To gain a better understanding of the nuclear functions of galectin-3 we now searched for putative galectin-3 binding partners in nuclear extracts and identified the heterogeneous ribonucleoprotein particle component hnRNPA2B1. Galectin-3 as well as hnRNPA2B1 co-localize in splicing factor enriched subnuclear speckles. Specific depletion of the two galectins, galectin-1 and ?3, affects mRNA-export from the nucleus as assessed by fluorescence in situ hybridization. Single knockdown of galectin-3 alters the splicing patterns of several genes, including the SET-oncogene, which is also affected in hnRNPA2B1-depleted cells.