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

• Published in: Molecular biology of the cell 2014-04, Vol.25 (7), p.977-991
• Main Authors: Mbom, Bertrade C, Siemers, Kathleen A, Ostrowski, Maggie A, Nelson, W James, Barth, Angela I M
• Format: Article
• Language: English
• Subjects: beta Catenin - metabolism; Casein Kinase I - metabolism; Cell Cycle Proteins - metabolism; Centrosome - metabolism; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; HCT116 Cells; HEK293 Cells; Humans; Mitosis; NIMA-Related Kinases; Phosphorylation; Polo-Like Kinase 1; Protein Serine-Threonine Kinases - metabolism; Protein Stability; Proto-Oncogene Proteins - metabolism; Sequence Deletion; Serine - metabolism; Spindle Apparatus - metabolism
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.E13-06-0349

β-Catenin is a multifunctional protein with critical roles in cell-cell adhesion, Wnt signaling, and the centrosome cycle. Whereas the regulation of β-catenin in cell-cell adhesion and Wnt signaling are well understood, how β-catenin is regulated at the centrosome is not. NIMA-related protein kinase 2 (Nek2), which regulates centrosome disjunction/splitting, binds to and phosphorylates β-catenin. Using in vitro and cell-based assays, we show that Nek2 phosphorylates the same regulatory sites in the N-terminus of β-catenin as glycogen synthase kinase 3β (GSK3β), which are recognized by a specific phospho-S33/S37/T41 antibody, as well as additional sites. Nek2 binding to β-catenin appears to inhibit binding of the E3 ligase β-TrCP and prevents β-catenin ubiquitination and degradation. Thus β-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 β-catenin. Taken together, these results identify a novel mechanism for regulating β-catenin stability that is independent of GSK3β and provide new insight into a pathway involving Plk1, Nek2, and β-catenin that regulates the centrosome cycle.