The SxxSS motif of T-cell factor-4 isoforms modulates Wnt/β-catenin signal activation in hepatocellular carcinoma cells

•TCF proteins represent key transcription factors in Wnt signaling.•TCF-4K (bearing the SxxSS) exhibits reduced transcriptional activity compared to TCF-4J (lacking the SxxSS) in HCC cells.•TCF-4K SxxSS mutants increase transcriptional activity and modify co-factors in the transcriptional complex.•Phosphorylation of the SxxSS motif mediated through HIPK2 causes suppression of TCF-4K activity.

T-cell factor (TCF) proteins represent key transcription factors in Wnt signaling. We show that the SxxSS motif in TCF-4 regulates transcriptional activity in HCC cells. TCF-4K mutants increased transcriptional activity compared to TCF-4K (bearing the SxxSS); the binding pattern of co-factors in TCF-4K mutants was similar to that in TCF-4J (lacking the SxxSS). TCF activity in TCF-4K cells was suppressed by homeodomain-interacting protein kinase 2 (HIPK2), but not in TCF-4J cells. Together, our data indicates that the SxxSS motif in TCF-4K regulates transcriptional activity by modifying co-factors in the β-catenin/TCF-4 transcriptional complex and these events may be mediated through HIPK2.