Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: A molecular switch for the Wnt pathway

摘要: The Wnt pathway controls numerous developmental processes via the β-catenin–TCF/LEF transcription complex. Deregulation of results in aberrant accumulation β-catenin nucleus, often leading to cancer. Normally, cytoplasmic associates with APC and axin is continuously phosphorylated by GSK-3β, marking it for proteasomal degradation. signaling considered prevent GSK-3β from phosphorylating β-catenin, thus causing its stabilization. However, mechanism action has not been resolved. Here we study regulation phosphorylation degradation pathway. Using mass spectrometry phosphopeptide-specific antibodies, show that a complex casein kinase I (CKI) induces at single site: serine 45 (S45). Immunopurified recombinant CKI phosphorylate vitro S45; inhibition suppresses this vivo. creates priming site both necessary sufficient initiate phosphorylation–degradation cascade. Wnt3A Dvl overexpression suppress S45 phosphorylation, thereby precluding initiation Thus, single, CKI-dependent event serves as molecular switch