Beta-Catenin is at the hub of multiple signaling pathways

β-Catenin is at the hub of multiple signaling pathways. Many signaling pathways regulate the stability or binding interactions of β-catenin. In the Wnt pathway, glycogen synthase kinase-3β (GSK3β) and casein kinase 1 (CK1) phosphorylate the N-terminal degron sequence of β-catenin to facilitate its destruction. The phosphatidylinositol-3-kinase (PI3K) and phosphatase and tensin homolog (PTEN) pathways also impinge upon β-catenin phosphorylation by regulating GSK3β activity. In addition, p53 induces the degradation of β-catenin through protein interactions involving Seven in absentia homolog 1 (Siah1), Siah interacting protein (SIP) and EBV-induced G-protein coupled receptor (Ebi), resulting in ubiquitination and degradation of β-catenin. Pin1 binds to β-catenin phosphorylated on S246P to prevent its association with adenomatous polyposis coli (APC). In the NF-κB pathway, IκB kinase (IKK)α and IKKβ phosphorylate β-catenin throughout the protein to activate and inhibit transcription, respectively, although the N-terminus is essential for IKKα regulation. Some proteins, such as those within the transforming growth factor beta (TGFβ) pathway and Sox17, regulate β-catenin in the nucleus by modulating its interaction with transcriptional co-activators Tcf/Lef. Other proteins, like enhancer of zeste homolog 2 (EZH2), interact with β-catenin to promote its translocation into the nucleus. A number of tyrosine kinases phosphorylate (both membrane bound and cytosolic) β-catenin to prevent its binding to the cadherin complex at the cell membrane. Src, epidermal growth factor receptor (EGFR), and erythroblastic leukemia viral oncogene-2 (ErbB2) have been shown or implicated to phosphorylate β-catenin on Y654, while Abelson tyrosine kinase (Abl) phosphorylates Y489. β-TrCP, beta-transducing repeat-containing protein; DKK, Dickkopf; Lgs, legless; LRP, low-density lipoprotein-related protein; MAPK, mitogen-activated protein kinase; NLK, Nemo-like kinase; Pygo2, pygopus homolog 2; sFRP, secreted frizzled-related protein; WIF, Wnt inhibitory factor.

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Key signaling nodes in mammary gland development and cancer: β-catenin. (2010) Angela Incassati, et al. Breast Cancer Res. 2010;12(6):213-213. Figure: F2. Homo sapiens

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