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J Cell Sci 2012 Feb 01;125Pt 3:561-9. doi: 10.1242/jcs.086173.
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Down's-syndrome-related kinase Dyrk1A modulates the p120-catenin-Kaiso trajectory of the Wnt signaling pathway.

Hong JY , Park JI , Lee M , Muñoz WA , Miller RK , Ji H , Gu D , Ezan J , Sokol SY , McCrea PD .

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.

PubMed ID: 22389395
PMC ID: PMC3367828
Article link: J Cell Sci
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: actl6a arvcf cdh3 ctnnd1 dyrk1a.2 myc odc1 sia1 tbx2 wnt11 zbtb33
Morpholinos: dyrk1a MO1

Article Images: [+] show captions
References [+] :
Altafaj, Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome. 2001, Pubmed