Nek2 phosphorylates and stabilizes ß-catenin at mitotic centrosomes downstream of Plk1.

ß-Catenin is a multifunctional protein with critical roles in cell-cell adhesion, Wnt signaling, and the centrosome cycle. Whereas the regulation of ß-catenin in cell-cell adhesion and Wnt signaling are well understood, how ß-catenin is regulated at the centrosome is not. NIMA-related protein kinase 2 (Nek2), which regulates centrosome disjunction/splitting, binds to and phosphorylates ß-catenin. Using in vitro and cell-based assays, we show that Nek2 phosphorylates the same regulatory sites in the N-terminus of ß-catenin as glycogen synthase kinase 3ß (GSK3ß), which are recognized by a specific phospho-S33/S37/T41 antibody, as well as additional sites. Nek2 binding to ß-catenin appears to inhibit binding of the E3 ligase ß-TrCP and prevents ß-catenin ubiquitination and degradation. Thus ß-catenin phosphorylated by Nek2 is stabilized and accumulates at centrosomes in mitosis. We further show that polo-like kinase 1 (Plk1) regulates Nek2 phosphorylation and stabilization of ß-catenin. Taken together, these results identify a novel mechanism for regulating ß-catenin stability that is independent of GSK3ß and provide new insight into a pathway involving Plk1, Nek2, and ß-catenin that regulates the centrosome cycle.

ß-catenin at the centrosome: discrete pools of ß-catenin communicate during mitosis and may co-ordinate centrosome functions and cell cycle progression.

Beta-catenin is a multifunctional protein with critical roles in cell-cell adhesion, Wnt-signaling and the centrosome cycle. Whereas the roles of ß-catenin in cell-cell adhesion and Wnt-signaling have been studied extensively, the mechanism(s) involving ß-catenin in centrosome functions are poorly understood. ß-Catenin localizes to centrosomes and promotes mitotic progression. NIMA-related protein kinase 2 (Nek2), which stimulates centrosome separation, binds to and phosphorylates ß-catenin. ß-Catenin interacting proteins involved in Wnt signaling such as adenomatous polyposis coli, Axin, and GSK3ß, are also localized at centrosomes and play roles in promoting mitotic progression. Additionally, proteins associated with cell-cell adhesion sites, such as dynein, regulate mitotic spindle positioning. These roles of proteins at the cell cortex and Wnt signaling that involve ß-catenin indicate a cross-talk between different sub-cellular sites in the cell at mitosis, and that different pools of ß-catenin may co-ordinate centrosome functions and cell cycle progression.