Interaction between Wnt/β-catenin and RAS-ERK pathways and an anti-cancer strategy via degradations of β-catenin and RAS by targeting the Wnt/β-catenin pathway

The canonical Wnt/β-catenin pathway. a In the absence of Wnt ligands, APC (adenomatous polyposis coli) and Axin are recruited into the “β-catenin destruction complex”. The phosphorylations by CK1α (casein kinase 1α) and GSK3β (glycogen synthase kinase 3β) recruit β？TrCP E3 linker (β-transducin repeat-containing protein, an E3 ubiquitin ligase), and subsequently degrade β？catenin via the proteasome. Low-cytoplasmic levels of β-catenin ensure in activation of TCF/LEF (T-cell factor/lymphoid enhancer factor) transcription factors and transcriptional repression of Wnt target genes. b In the accumulation of the extracellular Wnt ligands, the association of Axin with phosphorylated LRP5/6 (lipoprotein receptor-related protein 5/6) and recruitment of phosphorylated DVL (dishevelled) to FZD (frizzled) lead to the dissociation of the destruction complex. β-Catenin is stabilized, translocated into the nucleus, forms the complex with TCF or LEF, and subsequently activates the target genes. CCND1, cyclin D1; EGFR, epidermal growth factor receptor; LGR5, Leucine-rich repeat-containing G-protein coupled receptor 5; P, phosphorylation; U, ubiquitinatio