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

J Cell Sci. 2012 Feb 1;125(Pt 3):561-9. doi: 10.1242/jcs.086173.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • RNA, Small Interfering / genetics
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Repressor Proteins / metabolism*
  • Sequence Homology, Amino Acid
  • Transfection
  • Wnt Signaling Pathway / physiology*
  • Xenopus Proteins / genetics
  • Xenopus Proteins / metabolism*
  • Xenopus laevis / embryology
  • Xenopus laevis / genetics
  • Xenopus laevis / metabolism

Substances

  • Catenins
  • DNA Primers
  • Mutant Proteins
  • RNA, Small Interfering
  • Recombinant Proteins
  • Repressor Proteins
  • Xenopus Proteins
  • ZBTB33 protein, Xenopus
  • delta catenin
  • Dyrk1A protein, Xenopus
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases