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PTK7/Otk interacts with Wnts and inhibits canonical Wnt signalling
Hanna Peradziryi1, Nicole A Kaplan, Martina Podleschny
1Department of Developmental Biochemistry, Center for Molecular Physiology of the Brain, GZMB, University of Göttingen, Germany.
Abstract:
Wnt signalling is an evolutionarily conserved pathway that directs cell-fate determination and morphogenesis during metazoan development. Wnt ligands are secreted glycoproteins that act at a distance causing a wide range of cellular responses from stem cell maintenance to cell death and cell proliferation. How Wnt ligands cause such disparate responses is not known, but one possibility is that different outcomes are due to different receptors. Here, we examine PTK7/Otk, a transmembrane receptor that controls a variety of developmental and physiological processes including the regulation of cell polarity, cell migration and invasion. PTK7/Otk co-precipitates canonical Wnt3a and Wnt8, indicating a role in Wnt signalling, but PTK7 inhibits rather than activates canonical Wnt activity in Xenopus, Drosophila and luciferase reporter assays. Loss of PTK7 function activates canonical Wnt signalling and epistasis experiments place PTK7 at the level of the Frizzled receptor. In Drosophila, Otk interacts with Wnt4 and opposes canonical Wnt signalling in embryonic patterning. We propose a model where PTK7/Otk functions in non-canonical Wnt signalling by turning off the canonical signalling branch.
Insights
The transmembrane receptor PTK7/Otk inhibits canonical Wnt signaling, acting as a switch. Loss of PTK7/Otk function activates canonical Wnt pathways, suggesting its role in non-canonical Wnt signaling.
Area of Science:
- Developmental Biology
- Cell Signaling
- Molecular Biology
Background:
- Wnt signaling is crucial for metazoan development, controlling cell fate and morphogenesis.
- Wnt ligands trigger diverse cellular responses, but the underlying mechanisms are not fully understood.
- Receptor diversity may explain varied Wnt pathway outcomes.
Purpose of the Study:
- To investigate the role of the transmembrane receptor PTK7/Otk in Wnt signaling.
- To determine how PTK7/Otk influences canonical and non-canonical Wnt pathways.
- To elucidate the interaction between PTK7/Otk and Wnt ligands.
Main Methods:
- Co-precipitation assays to detect Wnt ligand interaction with PTK7/Otk.
- Functional assays in Xenopus and Drosophila, including loss-of-function studies.
- Luciferase reporter assays to quantify Wnt pathway activity.
- Epistasis experiments to position PTK7/Otk within the Wnt signaling cascade.
Main Results:
- PTK7/Otk co-precipitates with Wnt3a and Wnt8.
- PTK7/Otk inhibits canonical Wnt activity across multiple model systems.
- Loss of PTK7/Otk function leads to activation of canonical Wnt signaling.
- Epistasis data places PTK7/Otk upstream of or at the level of Frizzled receptors.
- PTK7/Otk interacts with Wnt4 and opposes canonical Wnt signaling in Drosophila embryonic patterning.
Conclusions:
- PTK7/Otk acts as an inhibitor of canonical Wnt signaling.
- PTK7/Otk likely functions within non-canonical Wnt signaling pathways.
- PTK7/Otk may serve as a regulatory switch, turning off the canonical Wnt branch.
- This provides a novel mechanism for diversifying Wnt signaling outcomes.
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