Regulation of β-Catenin Function by the IκB Kinases

Abstract

Both the ␤-catenin and the nuclear factor B (NF-B) proteins are important regulators of gene expression and cellular proliferation. Two kinases, IKK␣ and IKK␤, are critical activators of the NF-B pathway. Here we present evidence that these kinases are also important in the regulation of ␤-catenin function. IKK␣-and IKK␤-deficient mouse embryo fibroblasts exhibited different patterns of ␤-catenin cellular localization. IKK␤ decreases ␤-catenin-dependent transcriptional activation, while IKK␣ increases ␤-catenin-dependent transcriptional activity. IKK␣ and IKK␤ interact with and phosphorylate ␤-catenin using both in vitro and in vivo assays. Our results suggest that differential interactions of ␤-catenin with IKK␣ and IKK␤ may in part be responsible for regulating ␤-catenin protein levels and cellular localization and integrating signaling events between the NF-B and Wingless pathways.␤-Catenin, the mammalian homologue of the Drosophila armadillo protein, is a ubiquitously expressed protein that has at least two distinct roles in the cell. First, it participates in cell-cell adhesion by mediating the association of E-cadherin with the cytoskeleton (1, 2). Second, it is a critical downstream component of the Wnt 1 or Wingless signal transduction pathway (3-5). The Wnt family of secretory glycoproteins plays an important role in embryonic development, in the induction of cell polarity, and in the determination of cell fate. Deregulation of Wnt signaling disrupts axis formation in embryos (5-8) and is associated with multiple human malignancies (9).The current model of Wnt signaling indicates that the binding of the Wnt proteins to their receptor, frizzled, stabilizes ␤-catenin by inhibiting the activity of a serine/threonine kinase glycogen synthase kinase-3 or GSK-3␤ (9). GSK-3␤ is associated with ␤-catenin in a multiprotein complex that includes the adenomatous polyposis coli tumor suppressor protein (APC), axin or conductin, protein phosphatase 2A, and dishevelled. GSK-3␤ phosphorylation of residues in the amino terminus of ␤-catenin results in APC-mediated ␤-catenin degradation via the ubiquitin-proteosome pathway (10, 11). Increased levels of ␤-catenin are frequently found in colon cancer due to mutations in either the APC gene (12)(13)(14) or at residues in the amino terminus of ␤-catenin that are phosphorylated by . In the nucleus, ␤-catenin forms a complex with members of the T-cell factor (TCF)/lymphocyte-enhancer factor (LEF) family and activates gene expression of a variety of target genes (18 -23) including c-myc (24) and cyclin D1 (25, 26).NF-B comprises a family of transcription factors which are critical in activating the expression of genes involved in the immune and inflammatory response and in the regulation of cellular apoptosis (27, 28). NF-B is sequestered in the cytoplasm by a family of inhibitory proteins known as IB. Upon stimulation of this pathway by a variety of agents including IL-1 and TNF␣, the kinases IKK␣ and IKK␤ (29 -33) in conjunction with the scaffold protein IKK␥/NEMO (34 -36) l...

The pattern of β-catenin responsiveness within the mammary gland is regulated by progesterone receptor

“…␤-catenin is the central transducer of the canonical Wnt pathway and can also synergize with RANKL signaling (Fig. 8) (Fantl et al, 1999;Shtutman et al, 1999;Tetsu and McCormick, 1999;Cao et al, 2001;Lamberti et al, 2001;Rowlands et al, 2003). The observation that ⌬N89␤-catenin rescues alveologenesis but not side-branching in PR -/-mice is entirely consistent with previous findings that ␤-catenin signaling suppressors specifically impair alveologenesis (Hsu et al, 2001;Tepera et al, 2003).…”

Temporal pattern of NFκB activation influences apoptotic cell fate in a stimuli-dependent fashion

“…Similar findings in IKK knockout mice also suggest that NFκB plays an important role as an anti-apoptotic factor during liver development (Rudolph et al, 2000;Tanaka et al, 1999). Since β-catenin has also been shown to be a substrate of the IKK complex (Lamberti et al, 2001), we also evaluated whether expression of our various IκBα constructs could affect β-catenin levels by substrate competition with the IKK complex and in turn affect the apoptotic outcome. However, our result demonstrated no significant change in β-catenin levels following infection with Ad.IκBαAS, Ad.IκBα (S32/36A) or Ad.IκBα (Y42F) (data not shown).…”

Stabilized β-catenin promotes hepatocyte proliferation and inhibits TNFα-induced apoptosis

“…41 Interestingly, recent reports suggested that b-catenin could interact with NF-kB and IKK pathways, which might potentially affect cell apoptosis. 42,43 The interface between Wnt/b-catenin signaling pathway and TNFa pathway remains to be defined.…”