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 beta-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 beta-catenin activation. Instead, we show that each LRP6 PPPS/TP motif contributes in a combinatorial fashion to activate the canonical Wnt-beta-catenin pathway.
Wolf
Joshua
J
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892, USA.
Palmby
Todd R
TR
Gavard
Julie
J
Williams
Bart O
BO
Gutkind
J Silvio
JS
D001483:Base Sequence; D002460:Cell Line; D017124:Conserved Sequence; D017931:DNA Primers; D005455:Fluorescent Antibody Technique; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000737:chemistry / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D017931:DNA Primers; D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051153:Wnt Proteins; D051176:beta Catenin