Wnt signaling is a highly conserved and context-dependent signal transduction pathway that belongs to the so-called morphogens. Wnt signals are instrumental during development, but also play a central role in tissue homeostasis. For instance, in the intestine Wnt signaling is crucial for both stem cell maintenance and proliferation in the transient amplifying compartment 1. This Wnt-dependent stem cell regulatory role is observed in diverse adult tissues, but is not a general feature as Wnt signals can also drive differentiation of cells, such as mesenchymal stem cells (MSCs) 2. Wnt signaling can be divided into a canonical and a non-canonical pathway. The non-canonical pathway mainly mediates migration, while the canonical signals are mostly conveyed by β-catenin, a transcription factor that is actively repressed in the cytoplasm in the absence of Wnt signals. β-catenin levels are kept under control by a multi-protein complex composed of the tumor suppressor adenomatous polyposis coli (APC); two kinases, casein kinase 1 (CK1) and glycogen synthase kinase 3 beta (GSK3-β); and Axin2 that serves as a scaffold to hold the complex together. This complex allows CK1 and GSK3-β to phosphorylate β-catenin at specific serine and threonine residues, priming its recognition by the U3 ubiquitin ligase β-transducin repeat-containing protein (β-TRCP). Consequently, β-catenin is ubiquitinated and targeted for proteosomal degradation (Figure 1A). However, in the presence of extracellular Wnt ligands, β-catenin degradation is halted. Wnt binds the membrane-bound receptor complex formed by frizzled (Fzd) and low-density lipoprotein receptor-related protein 5/6 (LRP5/6). As a result, the destruction complex is dissolved by a still poorly understood mechanism. This allows β-catenin to accumulate in the cytosol and, subsequently, translocate into the nucleus. There, it associates with the lymphoid enhancer factor/T-cell factor (LEF/TCF) family of transcription factors, converting them from repressors to activators of transcription. These steps are followed by additional nuclear events that ultimately trigger a complex transcriptional program depending on the cellular context that will direct cell fate, cell proliferation, and stem cell maintenance or cellular differentiation (Figure 1B) (See review by MacDonald et al., 2009) 3.