Pharmacology of the WNT Signaling System

de Man, Saskia Madelon Ada, van Amerongen, Renée, Saskia Madelon Ada de Man, Renée van Amerongen

WNT/CTNNB1 signaling is crucial for balancing cell proliferation and differentiation in all multicellular animals. CTNNB1 accumulation is the hallmark of WNT/CTNNB1 pathway activation and the key downstream event in both a physiological and an oncogenic context. In the absence of WNT stimulation, the cytoplasmic and nuclear levels of CTNNB1 are kept low because of its sequestration and phosphorylation by the so-called destruction complex, which targets CTNNB1 for proteasomal degradation. In the presence of WNT proteins, or as a result of oncogenic mutations, this process is impaired and CTNNB1 levels become elevated.Here we discuss recent advances in our understanding of destruction complex activity and inactivation, focusing on the individual components and interactions that ultimately control CTNNB1 turnover (in the "WNT off" situation) and stabilization (in the "WNT on" situation). We especially highlight the insights gleaned from recent quantitative, image-based studies, which paint an unprecedentedly detailed picture of the dynamic events that control destruction protein complex composition and function. We argue that these mechanistic details may reveal new opportunities for therapeutic intervention and could result in the destruction complex re-emerging as a target for therapy in cancer.