title: Down's-syndrome-related kinase Dyrk1A modulates the p120-catenin-Kaiso trajectory of the Wnt signaling pathway.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, TX 77030, USA.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Hong
authors.forename: Jae-Il
authors.initials: JI
authors.lastname: Park
authors.forename: Moonsup
authors.initials: M
authors.lastname: Lee
authors.forename: William A
authors.initials: WA
authors.lastname: Muñoz
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Miller
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.forename: Dongmin
authors.initials: D
authors.lastname: Gu
authors.forename: Jerome
authors.initials: J
authors.lastname: Ezan
authors.forename: Sergei Y
authors.initials: SY
authors.lastname: Sokol
authors.forename: Pierre D
authors.initials: PD
authors.lastname: McCrea
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D051177:Catenins / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D060449:Wnt Signaling Pathway / Q000502:physiology*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D000095002:Delta Catenin
chemical_list: D051177:Catenins; D017931:DNA Primers; D050505:Mutant Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D012097:Repressor Proteins; D029867:Xenopus Proteins; C451401:ZBTB33 protein, Xenopus; C521805:Dyrk1A protein, Xenopus; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D000095002:Delta Catenin