Fig. 9: Model of Wnt signalosome assembly.

Signalosome complexes during different phases of Wnt signaling and corresponding interactions of the Axin scaffold with itself or its ligands (underneath); also shown are key phosphorylations (diamonds, priming phosphorylations; dots, effector phosphorylations) imparted by LRP6-associated kinases (Fig. 8h; see also text), as indicated by matching colors and arrows (top, arrows for Axin-GSK3 complexes omitted for clarity). (Left) Without Wnt, the β-catenin destruction complex is assembled by APC and Axin, which binds to GSK3 (through GIR, pale blue) and, jointly with CK1α, earmarks β-catenin for proteasomal degradation. CK1α also phosphorylates Axin LIRup (red dots) to promote its binding to LIRα (ochre) and formation of an intramolecular foldback that opposes binding between LIR (yellow) and LRP6; unphosphorylated PPPSPxS motifs are indicated by short lines. (Middle) Upon Wnt-dependent coupling of FZD and LRP6, a patch of high PIP₂ (green dots) is generated by Dishevelled in the plasma membrane near the receptor complex where PIP₂ activates the AP2 clathrin adaptor towards LRP6, thus promoting clustering of LRP6 and clathrin coating of the PIP₂ locale. Hence, LRP6 encounters cyclin Y-activated CDK following its AP2-dependent co-targeting to clathrin locales and is thus phosphorylated at S1490 (green diamonds) which enables Axin and GSK3 to dock at LRP6. AP2-driven clustering of LRP6 allows simultaneous binding of Axin and GSK3 to adjacent ctails and exposes Axin to co-targeted CK1γ which phosphorylates LIRα at S359 (brown diamonds) to prime Axin for a subsequent multi-pronged interaction with GSK3; phosphorylation of S359 may also promote Axin binding to LRP6, which would explain the agonist role of CK1 during Wnt signaling (see text); dark green dots, phosphorylations of PPPSPxS that render these motifs competitive inhibitors of GSK3, which promotes transduction of the Wnt signal to β-catenin. (Right) AAK1 phosphorylates AP2 (terracotta dot) at peripheral sites of clathrin locales to initiate localized endocytosis while simultaneously phosphorylating Axin PRTxR (terracotta dot) to promote its multi-pronged interaction with GSK3. This causes detachment of GSK3 from the receptor complex and thus presages termination of Wnt signaling.