title: DYRK1A binds to an evolutionarily conserved WD40-repeat protein WDR68 and induces its nuclear translocation.
abstract: DYRK1A is encoded in the Down's syndrome critical region on human chromosome 21, and plays an important role in the functional and developmental regulation of many types of cells, including neuronal cells. Here we have identified WDR68, an evolutionarily conserved protein with WD40-repeat domains, as a cellular binding partner of DYRK1A. WDR68 was originally identified in petunia as AN11 that controls the pigmentation of flowers by stimulating the transcription of anthocyanin biosynthetic genes. Experiments with RNA interference showed that WDR68 was indispensable for the optimal proliferation and survival of mammalian cultured cell, and WDR68 depletion induced cell apoptosis. DYRK1A and DYRK1B, but not DYRK2, DYRK3, or DYRK4, bound to endogenous and expressed WDR68. The N-terminal domain, but not the catalytic kinase domain or the C-terminal domain of DYRK1A, was responsible for the WDR68 binding. Deletions in the N-terminal or C-terminal region outside of the central WD40-repeats of WDR68 abolished its binding to DYRK1A, suggesting that WD40 repeats are not sufficient for the association with DYRK1A. Immunofluorescent staining revealed that WDR68 was distributed throughout the cell. Importantly, nuclear accumulation of WDR68 was observed upon co-expression of the wild type and a kinase-dead mutant of DYRK1A. Taken together, these results suggest that DYRK1A binds specifically to WDR68 in cells, and that the binding, but not the phosphorylation event, induces the nuclear translocation of WDR68.
authors.affiliation: Department of Cell and Developmental Biology, Kyoto University, Kyoto, Japan. ymiyata@lif.kyoto-u.ac.jp
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Miyata
authors.forename: Eisuke
authors.initials: E
authors.lastname: Nishida
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D017124:Conserved Sequence / Q000235:genetics; D019143:Evolution, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D014162:Transfection; D000097603:Dyrk Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C515143:DCAF7 protein, human