Activation of WNT and hedgehog pathways in MCL. (A) In the absence of WNT ligand, β-catenin is actively degraded through a protein complex called the “destruction box,” where GSK3β phosphorylates β-catenin, targeting it for degradation by the proteasome. Binding of WNT to Frizzled (FZD)– low density lipoprotein receptor-related protein (LRP) receptor complexes at the membrane, induces the formation of Dishevelled (DVL)–FZD complexes that sequester Axin and GSK3β, inhibiting the formation of the destruction box. This allows translocation of β-catenin to the nucleus where it dimerizes with TCF and LEF.¹³⁴  (B) Binding of SHH to patched (PTCH), allows smoothened (SMO) to transduce a signal into the cytoplasm that leads to the breakdown of a protein complex formed by Fused, SUFU, and the transcription factor GLI. GLI is thereby released and translocates into the nucleus.¹³⁵  Red symbols indicate molecules activated or overexpressed in MCL. Illustration by Paulette Dennis.