understanding Wnt/beta‐catenin signaling

Wnt signaling is essential for development and tissue homeostasis. Disruption of Wnt signal transduction causes abnormal embryogenesis and cancers. We are interested in the molecular composition and logic of Wnt transduction pathways. Protein phosphorylation is pivotal for Wnt signaling. We have characterized two key phosphorylation events in the canonical Wnt/beta‐catenin pathway. One is phosphorylation of the Wnt coreceptor, LDL receptor related protein 6 (LRP6). This phosphorylation leads to LRP6 activation and the initiation of Wnt signal transduction. The other is beta‐catenin phosphorylation, which results in beta‐catenin degradation and is inhibited upon Wnt signaling. 1). The mechanism of phosphorylation and activation of the Wnt coreceptor LRP6. We have shown that Wnt induces LRP6 phosphorylation at PPPS/TP motifs, and this phosphorylation is necessary and sufficient to trigger Wnt signaling. We have generated antibodies that specifically recognize phosphorylated LRP6. These antibodies are useful tools for detection of Wnt signaling activation in vivo and for identification of kinases involved in LRP6 phosphorylation. I will discuss our recent progress in studying Wnt‐induced LRP6 phosphorylation and identifying LRP6 kinases. 2). The mechanism of phosphorylation and degradation of beta‐catenin. We have demonstrated that two kinases, casein kinase 1 (CK1) and glycogen synthase kinase 3 (GSK3), sequentially phosphorylate beta‐catenin in a protein complex assembled by the scaffolding protein Axin. I will discuss how Wnt receptor activation may lead to inhibition of beta‐catenin phosphorylation, and our attempt to identify other key molecules via in vitro reconstitution.