Secreted Frizzled-related Protein 2 (sFRP2) Redirects Non-canonical Wnt Signaling from Fz7 to Ror2 during Vertebrate Gastrulation

• Published in: The Journal of biological chemistry 2016-06, Vol.291 (26), p.13730-13742
• Main Authors: Brinkmann, Eva-Maria, Mattes, Benjamin, Kumar, Rahul, Hagemann, Anja I.H., Gradl, Dietmar, Scholpp, Steffen, Steinbeisser, Herbert, Kaufmann, Lilian T., Özbek, Suat
• Format: Article
• Language: English
• Subjects: Animals; development; Developmental Biology; embryo; Fz7; Gastrula; HEK293 Cells; Humans; Membrane Proteins - genetics; Membrane Proteins - metabolism; papc; Receptor Tyrosine Kinase-like Orphan Receptors - genetics; Receptor Tyrosine Kinase-like Orphan Receptors - metabolism; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Ror2; sFRP2; Wnt signaling; Wnt Signaling Pathway - physiology; Wnt-5a Protein - genetics; Wnt-5a Protein - metabolism; Xenopus; Xenopus laevis; Xenopus Proteins - genetics; Xenopus Proteins - metabolism; zebrafish; Zebrafish - embryology; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.733766

Convergent extension movements during vertebrate gastrulation require a balanced activity of non-canonical Wnt signaling pathways, but the factors regulating this interplay on the molecular level are poorly characterized. Here we show that sFRP2, a member of the secreted frizzled-related protein (sFRP) family, is required for morphogenesis and papc expression during Xenopus gastrulation. We further provide evidence that sFRP2 redirects non-canonical Wnt signaling from Frizzled 7 (Fz7) to the receptor tyrosine kinase-like orphan receptor 2 (Ror2). During this process, sFRP2 promotes Ror2 signal transduction by stabilizing Wnt5a-Ror2 complexes at the membrane, whereas it inhibits Fz7 signaling, probably by blocking Fz7 receptor endocytosis. The cysteine-rich domain of sFRP2 is sufficient for Ror2 activation, and related sFRPs can substitute for this function. Notably, direct interaction of the two receptors via their cysteine-rich domains also promotes Ror2-mediated papc expression but inhibits Fz7 signaling. We propose that sFRPs can act as a molecular switch, channeling the signal input for different non-canonical Wnt pathways during vertebrate gastrulation.