title: Nek2 phosphorylates and stabilizes β-catenin at mitotic centrosomes downstream of Plk1.
abstract: 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.
authors: Department of Biology, Stanford University, Stanford, CA 94305 Department of Chemical Engineering, Stanford University, Stanford, CA 94305 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.
authors: Bertrade C
authors: BC
authors: Mbom
authors: Kathleen A
authors: KA
authors: Siemers
authors: Maggie A
authors: MA
authors: Ostrowski
authors: W James
authors: WJ
authors: Nelson
authors: Angela I M
authors: AI
authors: Barth
mesh_terms: D047389:Casein Kinase I / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D018385:Centrosome / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D008938:Mitosis; D000072379:NIMA-Related Kinases; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D055550:Protein Stability; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017384:Sequence Deletion; D012694:Serine / Q000378:metabolism; D008941:Spindle Apparatus / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D047389:Casein Kinase I; D018797:Cell Cycle Proteins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012694:Serine; D051176:beta Catenin; D000097869:Polo-Like Kinase 1; C000605506:GSK3B protein, human; C089441:NEK2 protein, human