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Multiple PPPS/TP motifs act in a combinatorial fashion to transduce Wnt signaling through LRP6
Author(s) -
Wolf Joshua,
Palmby Todd R.,
Gavard Julie,
Williams Bart O.,
Gutkind J. Silvio
Publication year - 2008
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2007.12.013
Subject(s) - lrp6 , wnt signaling pathway , lrp5 , frizzled , mutant , microbiology and biotechnology , beta catenin , chemistry , biology , signal transduction , computational biology , genetics , gene
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.