This simplification is reasonable for canonical WNT signaling, because crucial events, like AXIN binding, mainly depend on LRP6 and its activation through phosphorylation .

We further employ a simplified representation of LRP6 phosphorylation .

LRP6 has to be phosphorylated at several phosphorylation sites to recruit and bind AXIN.

One of the key mechanisms of the WNT signal transduction is the formation of a large pro-tein-receptor complex, called signalosome, in response to the extracellular WNT stimulus [9, the signalosome triggers the phosphorylation of several intracellular phosphorylation sites (mainly PPSPXS motifs) in the cytosolic tail of LRP6, generating high-density platforms for the recruitment of AXIN [11—13].

As demonstrated by earlier and recent studies, the deployment of lipid rafts from the plasma membrane prevents the raft dependent LRP6 phosphorylation and thereby inhibits the WNT induced receptor activation and subsequent signal transduction [15, 17] , which could eXplain the inhibition of WNT/fi-catenin signaling by MbCD treatment after 3 hours.

This model neglects important processes like lipid rafts dynamics, receptor clustering and phosphorylation and further employs some unphysiological parameter values, in particular the total number of Frizzled receptors has been fitted to an exceedingly low molecule number, i.e., 30.

Apparently, the localization of LRP6 in lipid rafts is crucial for its successful phosphorylation , implying a major impact of lipid rafts on the activation of signalosome, hence WNT/fi-catenin signaling [15, 17].