Fig. 1.

Canonical and Non-canonical Wnt Signaling in Cancer

Both canonical and non-canonical Wnt ligands require Porcupine activity for secretion. Canonical Wnts bind Frizzled receptors in complex with LRP5/6 to activate downstream signaling by phosphorylation and stabilization of β-catenin, which enters the nucleus to activate gene transcript via TCF/LEFs. Non-canonical Wnts also act via Frizzled receptors, activating ROR1/2 or recruiting Daam1 to activate the planar cell polarity (PCP) pathways, which can activate gene transcription or promote actin cytoskeleton rearrangements. Both pathways are subject to extracellular regulation, with R-spondins (RSPO) potentiating canonical signaling, and the ubiquitin-ligase RNF43 (or its close relative ZNRF3) and Dkk acting as negative regulators (depicted in red). sFRPs may act as positive or negative regulators of canonical signalling depending on context. sFRPs and RNF43 can also regulate non-canonical signaling, although Dkks have been shown to activate PCP pathways, in one of several examples of cross-talk between different Wnt pathways. LRP: low-density lipoprotein receptor-related protein, APC: adenenomatous polyposis coli, GSK3β: Glycogen synthase kinase 3β, CK1α: casein kinase 1α, Daam1: dishevelled associated activator of morphogenesis 1, Dvl: dishevelled; ROR1/2, receptor-tyrosine kinase-like orphan receptor 1/2, TCF/LEF: transcription factor/lymphoid enhancer binding factors, sFRP: secreted frizzled-related protein, Dkk; Dikkopf.