Casein kinase 1 delta functions at the centrosome to mediate Wnt-3a-dependent neurite outgrowth

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) delta/epsilon inhibitor IC261. Small interfering RNAs targeting either CK1 delta or CK1 epsilon decreased Dvl phosphorylation, but only knockdown of CK1 delta blocked neurite outgrowth. CK1 delta but not CK1 epsilon was detected at the centrosome, an organelle associated with neurite formation. Deletion analysis mapped the centrosomal localization signal (CLS) of CK1 delta to its C-terminal domain. A fusion protein containing the CLS and EGFP displaced full-length CK1 delta from the centrosome and inhibited Wnt-3a-dependent neurite outgrowth. In contrast to wild-type CK1 epsilon, a chimera comprised of the kinase domain of CK1 epsilon and the CLS of CK1 delta localized to the centrosome and rescued Wnt-3a-dependent neurite outgrowth suppressed by CK1 delta knockdown. These results provide strong evidence that the centrosomal localization of CK1 delta is required for Wnt-3a-dependent neuritogenesis.