Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway.
By S. Amit, A. Hatzubai, Yaara Birman, Jens S. Andersen, E. Ben-Shushan, Matthias Mann, Y. Ben‐Neriah, I. Alkalay. Genes & Development, 2002
821 citations recorded by the source corpus.
The Wnt pathway controls numerous developmental processes via the beta-catenin-TCF/LEF transcription complex. Deregulation of the pathway results in the aberrant accumulation of beta-catenin in the nucleus, often leading to cancer. Normally, cytoplasmic beta-catenin associates with APC and axin and is continuously phosphorylated by GSK-3beta, marking it for proteasomal degradation. Wnt signaling is considered to prevent GSK-3beta from phosphorylating beta-catenin, thus causing its stabilization. However, the Wnt mechanism of action has not been resolved. Here we study the regulation of beta-catenin phosphorylation and degradation by the Wnt pathway. Using mass spectrometry and phosphopeptide-specific antibodies, we show that a complex of axin and casein kinase I (CKI) induces beta-catenin phosphorylation at a single site: serine 45 (S45). Immunopurified axin and recombinant CKI phosphorylate beta-catenin in vitro at S45; CKI inhibition suppresses this phosphorylation in vivo. CKI phosphorylation creates a priming site for GSK-3beta and is both necessary and sufficient to initiate the beta-catenin phosphorylation-degradation cascade. Wnt3A signaling and Dvl overexpression suppress S45 phosphorylation, thereby precluding the initiation of the cascade. Thus, a single, CKI-dependent phosphorylation event serves as a molecular switch for the Wnt pathway.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/09cbb980213d8176a8603e155894f94452c30871
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Citations in the corpus
- Functional redundancy of GSK-3α and GSK-3β in wnt/β-catenin signaling shown by using an allelic series of embryonic stem cell lines (2007, methodology): “Phosphorylation of S45 has been suggested to be the switch which regulates β-catenin phosphorylation and subsequent degradation (Amit et al., 2002).”
- Wnt signaling in the intestinal epithelium: from endoderm to cancer. (2005, background): “In the absence of Wnts, the scaffolding proteins APC and Axin/Axin2 sequester -catenin allowing casein kinase I (CKI) to phosphorylate the N terminus of -catenin at Ser S45, a residue often mutated in cancers (Amit et al. 2002; Liu et al. 2002).”
- Wnt signaling in development and tissue homeostasis (2018, background): “…is composed of the scaffolding proteins Axin (Behrens, 1998; Hart et al., 1998) and APC (Munemitsu et al., 1995; Rubinfeld et al., 1993), and the kinases CK1 α (Amit et al., 2002; Liu et al., 2002; Rubinfeld et al., 1996) and GSK3 α / β (Amit et al., 2002; Liu et al., 2002; Rubinfeld et al., 1996).”
- GSK-3: tricks of the trade for a multi-tasking kinase (2003, background): “Five groups have recently determined that β-catenin is also a primed substrate for GSK-3, with casein kinase I (CKI) acting as the priming kinase (Amit et al., 2002; Hagen et al., 2002; Hagen and Vidal-Puig, 2002; Liu et al., 2002; Sakanaka, 2002; Yanagawa et al., 2002).”
- E-cadherin, β-catenin, and ZEB1 in malignant progression of cancer (2009, background): “This destruction complex targets β-catenin for proteasomal breakdown by CK1- and GSK3β-dependent phosphorylation of N-terminal serin/threonin residues [45–51] (Fig.”
- Casein Kinase Iε Modulates the Signaling Specificities of Dishevelled (2004, methodology): “Epistasis experiments in Xenopus embryos suggest that CKIε functions between Dvl and GSK3 (40).”