title: Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-dependent neurite outgrowth.
abstract: Previously we determined that Dishevelled-2/3 (Dvl) mediate Wnt-3a-dependent neurite outgrowth in Ewing sarcoma family tumor cells. Here we report that neurite extension was associated with Dvl phosphorylation and that both were inhibited by the casein kinase 1 (CK1) δ/ε inhibitor IC261. Small interfering RNAs targeting either CK1δ or CK1ε decreased Dvl phosphorylation, but only knockdown of CK1δ blocked neurite outgrowth. CK1δ but not CK1ε was detected at the centrosome, an organelle associated with neurite formation. Deletion analysis mapped the centrosomal localization signal (CLS) of CK1δ to its C-terminal domain. A fusion protein containing the CLS and EGFP displaced full-length CK1δ from the centrosome and inhibited Wnt-3a-dependent neurite outgrowth. In contrast to wild-type CK1ε, a chimera comprised of the kinase domain of CK1ε and the CLS of CK1δ localized to the centrosome and rescued Wnt-3a-dependent neurite outgrowth suppressed by CK1δ knockdown. These results provide strong evidence that the centrosomal localization of CK1δ is required for Wnt-3a-dependent neuritogenesis.
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yoshimi Endo
authors.initials: YE
authors.lastname: Greer
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Rubin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D048149:Casein Kinase 1 epsilon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D018385:Centrosome / Q000378:metabolism*; D004252:DNA Mutational Analysis; D000072261:Dishevelled Proteins; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016501:Neurites / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; C000606582:Dvl2 protein, mouse; D007527:Isoenzymes; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D048149:Casein Kinase 1 epsilon; D048148:Casein Kinase Idelta