Multiple PPPS/TP motifs act in a combinatorial fashion to transduce Wnt signaling through LRP6

Binding of Wnt to Frizzled, and either of two members of the low‐density‐lipoprotein receptor‐related protein family, LRP5/6, leads to β‐catenin activation by a poorly understood mechanism. LRP5/6 exhibit five highly conserved PPPS/TP motifs in their intracellular region, among which the first PPPS/TP site is rapidly phosphorylated upon Wnt stimulation. By the use of full‐length LRP6 mutants harboring multiple mutations involving the five PPPS/TP motifs, we found that this first PPPS/TP phosphoacceptor site is alone not sufficient or strictly necessary for β‐catenin activation. Instead, we show that each LRP6 PPPS/TP motif contributes in a combinatorial fashion to activate the canonical Wnt‐β‐catenin pathway.