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Glycogen synthase kinase-3β (GSK-3β) is a multifunctional serine/threonine kinase and regulates a variety of biological processes. Recent studies show GSK-3β can regulate pre-mRNA processing and transcription through phosphorylation of multiple splicing factors, but the detailed mechanism is still undetermined. In this study, we further proved that GSK-3β could specifically co-localize with SC35 in nuclear speckles depending on its kinase activity. Immunofluorescence and FISH studies showed the activity of nuclear GSK-3β regulated the assembly of nuclear speckles and consequently modulated the post-transcriptional processing of mRNA. In addition, GSK-3β phosphorylated SC35 and promoted its hyperphosphorylation, in which the unique C-terminal sequences were particularly important to efficiently sequential multiple phosphorylation of SC35. Hyperphosphorylated SC35 converged into cluster and lost its ability to perform splicing in nuclear speckles. More importantly, the nuclear GSK-3β activity could be a part of Wnt/β-catenin signaling activation by TCF4 and might take part in embryonic or tumorigenesis of cells.