A specific isoform of casein kinase 1 (CK1) localizes to the centrosome to promote neurite extension, Greer and Rubin reveal.
The signaling protein Wnt-3a stimulates rapid neurite outgrowth from certain cell lines by activating the effector proteins Dishevelled (Dvl) 2 and 3. Dvl proteins’ downstream effects can be modulated by phosphorylation. After finding that Dvl-2 and -3 were phosphorylated during Wnt-3a–induced neurite extension, Greer and Rubin screened a panel of small molecule inhibitors to identify the responsible protein kinases.
IC261, an inhibitor of the closely related CK1 isoforms δ and ε, blocked Wnt-3a–induced neurite outgrowth and Dvl-2/3 phosphorylation. Knocking down either kinase by RNAi also reduced Dvl-2/3 phosphorylation, yet the two isoforms had opposing effects on neurite formation. Cells lacking CK1δ no longer grew neurites in response to Wnt-3a, whereas CK1ε depletion prompted neurite extension in the absence of Wnt ligand, suggesting that this isoform usually inhibits neurite growth.
Greer and Rubin found that, unlike CK1ε, CK1δ localized strongly to the centrosome, an organelle that controls neurite outgrowth in many types of neurons. Blocking this localization prevented Wnt-3a from inducing neurite extension. CK1δ was targeted to the centrosome by a region in its C terminus; substituting this centrosomal localization signal for the C-terminal domain of CK1ε allowed that isoform to promote neurite formation in place of CK1δ, indicating that location is the key determinant of the isoforms’ different activities.
Many Wnt signaling pathway proteins localize to centrosomes. The authors now want to investigate whether they cooperate with CK1δ to drive neurite outgrowth and other centrosome functions such as ciliogenesis.