The postsynaptic density 95/disc-large/zona occludens protein syntenin directly interacts with frizzled 7 and supports noncanonical Wnt signaling.
Wnt signaling pathways are essential for embryonic patterning, and they are disturbed in a wide spectrum of diseases, including cancer. An unresolved question is how the different Wnt pathways are supported and regulated. We previously established that the postsynaptic density 95/disc-large/zona occludens (PDZ) protein syntenin binds to syndecans, Wnt coreceptors, and known stimulators of protein kinase C (PKC)alpha and CDC42 activity. Here, we show that syntenin also interacts with the C-terminal PDZ binding motif of several Frizzled Wnt receptors, without compromising the recruitment of Dishevelled, a key downstream Wnt-signaling component. Syntenin is coexpressed with cognate Frizzled during early development in Xenopus. Overexpression and down-regulation of syntenin disrupt convergent extension movements, supporting a role for syntenin in noncanonical Wnt signaling. Syntenin stimulates c-jun phosphorylation and modulates Frizzled 7 signaling, in particular the PKCalpha/CDC42 noncanonical Wnt signaling cascade. The syntenin-Frizzled 7 binding mode indicates syntenin can accommodate Frizzled 7-syndecan complexes. We propose that syntenin is a novel component of the Wnt signal transduction cascade and that it might function as a direct intracellular link between Frizzled and syndecans.
Luyten
Annouck
A
Department of Human Genetics, K.U. Leuven, B-3000 Leuven, Belgium.
Mortier
Eva
E
Van Campenhout
Claude
C
Taelman
Vincent
V
Degeest
Gisèle
G
Wuytens
Gunther
G
Lambaerts
Kathleen
K
David
Guido
G
Bellefroid
Eric J
EJ
Zimmermann
Pascale
P
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D051157:Frizzled Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor; D017386:Sequence Homology, Amino Acid; D020349:Surface Plasmon Resonance; D053667:Syndecans / Q000235:genetics / Q000378:metabolism; D053676:Syntenins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D029867:Xenopus Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
D018076:DNA, Complementary; C115810:FZD7 protein, human; D051157:Frizzled Receptors; D016755:Proto-Oncogene Proteins c-jun; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D053667:Syndecans; D053676:Syntenins; D051153:Wnt Proteins; D029867:Xenopus Proteins