Figure 6. Proposed mechanism by which FZD2 blockade affects NB cell behavior.

Simplified schematic view of β-catenin-dependent and -independent signaling pathways and the crosstalk between each other. Blue boxes indicate inhibited signaling factors and actions, red boxes depict activated signaling factors and actions following FZD2 blockade, which were revealed in this study. Wnt3a activates the β-catenin pathway by interacting with FZD2 and LRP6. When Wnt5a acts on FZD2 it may compete with Wnt3a, thereby inhibiting the β-catenin pathway. However, Wnt5a activates the Rac/JNK pathways. Downregulation of FZD2 inhibits the β-catenin pathway and the Rac/JNK pathways in NB cells. Blocking the action of Wnt5a on these pathways by blocking FZD2 could promote the activation of other β-catenin-independent Wnt pathways. Consequently, increased availability of Wnt5a protein may interact with receptor ROR1/2 or FZD to activate the PI3K/AKT and PKC pathway, leading to the activation of target genes, which normally suppress proliferation and migration. These actions, perhaps along with modulation of the activity of other non-canonical pathways (e.g. Rac/JNK), mediate the anti-proliferative and anti-migratory effects of Wnts following FZD2 blockade. In addition, Wnts acting via FZD and growth factor receptors also activate ERK. It is unclear, whether Wnt3a may also activate a β-catenin-independent pathway and/or contributes to ERK-activation. Phosphorylation of ERK alone or alteration of the p-ERK/p-AKT ratio in turn may regulate proliferation depending on the signaling strength thus counteracting or supporting the anti-proliferative effects of FZD2 blockade.