Down's-syndrome-related kinase Dyrk1A modulates the p120-catenin-Kaiso trajectory of the Wnt signaling pathway

• Published in: Journal of cell science Vol. 125; no. Pt 3; pp. 561 - 569
• Main Authors: Hong, Ji Yeon, Park, Jae-Il, Lee, Moonsup, Muñoz, William A, Miller, Rachel K, Ji, Hong, Gu, Dongmin, Ezan, Jerome, Sokol, Sergei Y, McCrea, Pierre D
• Format: Journal Article
• Language: English
• Published: England Company of Biologists 01.02.2012
• Subjects: Amino Acid Sequence; Animals; Base Sequence; Catenins - genetics; Catenins - metabolism; DNA Primers - genetics; Down Syndrome - genetics; Down Syndrome - metabolism; Gene Expression Regulation, Developmental; HEK293 Cells; Humans; Molecular Sequence Data; Mutant Proteins - genetics; Mutant Proteins - metabolism; Phosphorylation; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Repressor Proteins - metabolism; RNA, Small Interfering - genetics; Sequence Homology, Amino Acid; Short Reports; Transfection; Wnt Signaling Pathway - physiology; Xenopus laevis; Xenopus laevis - embryology; Xenopus laevis - genetics; Xenopus laevis - metabolism; Xenopus Proteins - genetics; Xenopus Proteins - metabolism
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.086173

The Wnt pathways contribute to many processes in cancer and development, with β-catenin being a key canonical component. p120-catenin, which is structurally similar to β-catenin, regulates the expression of certain Wnt target genes, relieving repression conferred by the POZ- and zinc-finger-domain-containing transcription factor Kaiso. We have identified the kinase Dyrk1A as a component of the p120-catenin-Kaiso trajectory of the Wnt pathway. Using rescue and other approaches in Xenopus laevis embryos and mammalian cells, we found that Dyrk1A positively and selectively modulates p120-catenin protein levels, thus having an impact on p120-catenin and Kaiso (and canonical Wnt) gene targets such as siamois and wnt11. The Dyrk1A gene resides within the Down's syndrome critical region, which is amplified in Down's syndrome. A consensus Dyrk phosphorylation site in p120-catenin was identified, with a mutant mimicking phosphorylation exhibiting the predicted enhanced capacity to promote endogenous Wnt-11 and Siamois expression, and gastrulation defects. In summary, we report the biochemical and functional relationship of Dyrk1A with the p120-catenin-Kaiso signaling trajectory, with a linkage to canonical Wnt target genes. Conceivably, this work might also prove relevant to understanding the contribution of Dyrk1A dosage imbalance in Down's syndrome.