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

Ji Yeon Hong, Jae Il Park, Moonsup Lee, William A. Muñoz, Rachel K. Miller, Hong Ji, Dongmin Gu, Sergei Y. Sokol, Pierre D. McCrea

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)561-569
Number of pages9
JournalJournal of Cell Science
Volume125
Issue number3
DOIs
StatePublished - 1 Feb 2012

Keywords

  • Dyrk1A
  • Hipk
  • P120-catenin
  • Siamois
  • Wnt11

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