Concentration-dependent activation of Wnt pathways. Wnt/β-catenin signaling is activated by high concentrations of Wnt ligands, resulting in the stabilization of β-catenin (left). Binding of Wnt protein results in LRP6/Fz heterodimer formation. Intracellular components of canonical Wnt signaling thereby are recruited to the receptor complex including disheveled (dsh), axin, and GSK3β. As a consequence, β-catenin accumulates in the cytoplasm, enters the nucleus, and interacts with transcription factors such as TCF/LEF, resulting in target gene activation. In contrast, Wnt/Ca²⁺ signaling is favored by lower concentrations of Wnt ligands (right). Wnt/Frizzled interaction results in a G protein (orange circle)-mediated activation of phospholipase Cβ (PLC) that generates diacylglycerol (DAG) and inositol-3,4,5-trisphosphate (IP₃). IP₃ production results in release of calcium ions from the ER that in turn activate CamKII. Target genes are indicated as in Nalesso et al. (2011). Both pathways reciprocally inhibit each other.