Activation/Proliferation-associated Protein 2 (Caprin-2) Positively Regulates CDK14/Cyclin Y-mediated Lipoprotein Receptor-related Protein 5 and 6 (LRP5/6) Constitutive Phosphorylation.

Low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are co-receptors for Wnt ligands. Upon ligand binding, LRP5/6 undergo glycogen synthase kinase 3 (GSK3)/casein kinase I (CKI)-mediated phosphorylation at multiple PPP(S/T)P motifs in the intracellular domain, which is essential for canonical Wnt signal transduction. On the other hand, in the Wnt-off state, the mitosis-specific CDK14-Cyclin Y kinase complex phosphorylates Ser-1490 of LRP5/6 at G2/M, thereby priming the receptor for Wnt-induced phosphorylation. However, it remains unclear how CDK14/Cyclin Y is recruited to LRP5/6 and whether there are other cofactors involved in this process. Previously, we identified Caprin-2 as a positive regulator of canonical Wnt signaling by promoting GSK3-depedent LRP5/6 phosphorylation upon Wnt stimulation. Here we uncovered that Caprin-2 positively regulates constitutive LRP5/6 Ser-1490 phosphorylation by complexing with CDK14/Cyclin Y. Caprin-2-mediated LRP5/6 phosphorylation is cell cycle-dependent in a pattern similar to that of CDK14/Cyclin Y-dependent LRP5/6 phosphorylation. Moreover, knockdown of Caprin-2 disrupts not only the interaction between CDK14 and Cyclin Y but also the interaction between CDK14/Cyclin Y and LRP6. Overall, our findings revealed an unrecognized role of Caprin-2 in facilitating LRP5/6 constitutive phosphorylation at G2/M through forming a quaternary complex with CDK14, Cyclin Y, and LRP5/6.