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Vol. 19, Issue 4, 1594-1604, April 2008

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The Postsynaptic Density 95/Disc-Large/Zona Occludens Protein Syntenin Directly Interacts with Frizzled 7 and Supports Noncanonical Wnt Signaling

Annouck Luyten^*,, Eva Mortier^*,, Claude Van Campenhout, Vincent Taelman, Gisèle Degeest^*,, Gunther Wuytens^*,, Kathleen Lambaerts^*,, Guido David^*,, Eric J. Bellefroid, and Pascale Zimmermann^*,

*Department of Human Genetics, K.U. Leuven, B-3000 Leuven, Belgium; Department for Molecular and Developmental Genetics, VIB, B-3000 Leuven, Belgium; and Institut de Biologie et de Medecine Moléculaires, Université Libre de Bruxelles, B-6041 Gosselies, Belgium

Submitted August 28, 2007; Revised January 3, 2008; Accepted January 30, 2008
Monitoring Editor: Carl-Henrik Heldin

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) 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 PKC/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.

Address correspondence to: Pascale Zimmermann (pascale.zimmermann{at}med.kuleuven.be)