Notch and Wnt signaling pathways. (A) Notch pathway: When ligands of the Delta (Delta1-3) or Jagged (Jagged 1-2) families bind to the Notch receptor, proteolytic events involving γ-secretase lead to release and translocation of the intracellular domain of the receptor (NICD) to the nucleus. Subsequently, NICD will form a complex with the transcription factor CSL and cofactors of the Mastermind-like (MAML) family to activate transcription of target genes.138 (B) Wnt pathway: Wnt signaling is initiated when a ligand binds to the Frizzled and lipoprotein receptor-related protein (LRP) receptors at the cell surface. In the absence of Wnt ligands, the downstream signal transducer β-catenin is trapped by adenomatous polyposis coli (APC) and Axin in a destruction complex, where it is phosphorylated by casein-kinase 1α (CK1α) and glycogen synthase kinase (GSK3β). Phosphorylation ultimately leads to ubiquitination and degradation of β-catenin. On ligand binding, Frizzled forms a complex with disheveled (Dsh), whereas LRP is phosphorylated, resulting in Axin relocation to the cell membrane. Subsequently, the destruction complex is dispersed and β-catenin accumulates and translocates to the nucleus where it interacts with the T-cell factor/lymphoid enhancer factor (TCF) transcription factors to regulate gene expression.139,140
