Figure 1.

Overview of canonical and non-canonical Wnt signaling. (a) In canonical Wnt signaling, absence of Wnt ligands (Wnt signaling inactive state, left) leads to phosphorylation of β-catenin by the destruction complex, which contains the scaffold protein Axin, APC and the kinases GSK3β and casein kinase (CK1α). In this state, β-catenin is phosphorylated by GSK3β, ubiquitinated by β-TrCP²⁰⁰ and targeted for proteasomal degradation. In the absence of nuclear β-catenin, a repressive complex containing TCF/LEF and transducing-like enhancer protein (TLE/Groucho) recruits HDACs to repress target genes. The canonical pathway is activated upon binding of secreted Wnt ligands (for example, Wnt3a and Wnt1) to Fzd receptors and LRP co-receptors (Wnt signaling active, right). LRP receptors are then phosphorylated by CK1α and GSK3β, which recruits Dishevelled (Dvl) proteins to the plasma membrane where they polymerize and are activated.²⁰¹ The Dvl polymers inactivate the destruction complex, for example, by sequestration in multivesicular bodies. This results in stabilization and accumulation of β-catenin which then translocates into the nucleus. There, β-catenin forms an active complex with LEF (lymphoid enhancer factor) and TCF (T-cell factor) proteins by displacing TLE/Groucho complexes and recruitment of histone modifying co-activators such as CBP/p300, BRG1, BCL9 and Pygo (reviewed in Lien and Fuchs⁴⁸). This transcriptional switch leads to a change of multiple cellular processes.^{49, 202} (b) Non-canonical Wnt signaling is defined by β-catenin-independent mechanisms of signal transduction. During Wnt/PCP signaling, Wnt ligands bind to the ROR-Frizzled receptor complex to recruit and activate Dvl.²⁰³ Dvl binds to the small GTPase Rho by de-inhibition of the cytoplasmic protein DAAM1 (Dvl associated activator of morphogenesis 1).²⁰⁴ The small GTPase Rac1 and Rho together trigger ROCK (Rho kinase) and JNK. This leads to rearrangements of the cytoskeleton and/or transcriptional responses via for example, ATF2 (activating transcription factor 2).²⁰⁵ Next to Dvl, Vangl, a key member of Wnt/PCP signaling is activated by phosphorylation in a Wnt5a-dependent manner.²⁰⁶ Wnt/Ca2+ signaling is initiated by G-protein triggered phospholipase C activity²⁰⁷ leading to intracellular calcium fluxes and downstream calcium dependent cytoskeletal and/or transcriptional responses.²⁰⁸