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Updated: Oct 14, 2025
Modeling Paracrine Noncanonical Wnt Signaling In Vitro
Published on: December 10, 2021
Bridging the gap between non-canonical and canonical Wnt signaling through Vangl2
Ian James Bell1, Matthew Sheldon Horn1, Terence John Van Raay1
1Department of Molecular and Cellular Biology, University of Guelph, 50 Stone Rd. E, Guelph, ON, Canada N1G 2W1.
Abstract:
Non-canonical Wnt signaling (encompassing Wnt/PCP and WntCa2+) has a dual identity in the literature. One stream of research investigates its role in antagonizing canonical Wnt/β-catenin signaling in cancer, typically through Ca2+, while the other stream investigates its effect on polarity in development, typically through Vangl2. Rarely do these topics intersect or overlap. What has become clear is that Wnt5a can mobilize intracellular calcium stores to inhibit Wnt/β-catenin in cancer cells but there is no evidence that Vangl2 is involved in this process. Conversely, Wnt5a can independently activate Vangl2 to affect polarity and migration but the role of calcium in this process is also limited. Further, Vangl2 has also been implicated in inhibiting Wnt/β-catenin signaling in development. The consensus is that a cell can differentiate between canonical and non-canonical Wnt signaling when presented with a choice, always choosing non-canonical at the expense of canonical Wnt signaling. However, these are rare events in vivo. Given the shared resources between non-canonical and canonical Wnt signaling it is perplexing that there is not more in vivo evidence for cross talk between these two pathways. In this review we discuss the intersection of non-canonical Wnt, with a focus on Wnt/PCP, and Wnt/β-catenin signaling in an attempt to shed some light on pathways that rarely meet at a crossroads in vivo.
Insights
Non-canonical Wnt signaling pathways, including Wnt/PCP and WntCa2+, have distinct roles in cancer and development. This review explores their intersection, focusing on Wnt/β-catenin signaling crosstalk.
Area of Science:
- Cellular Biology
- Developmental Biology
- Cancer Biology
Background:
- Non-canonical Wnt signaling, encompassing Wnt/Planar Cell Polarity (PCP) and Wnt/Ca2+, exhibits distinct roles in biological contexts.
- Research often separates its function in antagonizing canonical Wnt/β-catenin signaling in cancer (via Ca2+) from its role in developmental polarity (via Vangl2).
Purpose of the Study:
- To review and discuss the intersection of non-canonical Wnt signaling pathways, specifically Wnt/PCP, with Wnt/β-catenin signaling.
- To investigate the limited in vivo evidence for crosstalk between these pathways despite shared molecular resources.
Main Methods:
- Literature review and synthesis of existing research on Wnt signaling pathways.
- Analysis of studies investigating Wnt5a's role in calcium mobilization and Vangl2 activation.
- Examination of evidence for Wnt/β-catenin inhibition by non-canonical pathways in both cancer and development.
Main Results:
- Wnt5a mobilizes intracellular calcium to inhibit Wnt/β-catenin in cancer cells, independent of Vangl2.
- Wnt5a independently activates Vangl2 for polarity and migration, with limited calcium involvement.
- Vangl2 also inhibits Wnt/β-catenin signaling during development.
Conclusions:
- Cells can distinguish between canonical and non-canonical Wnt signaling, favoring non-canonical pathways.
- The limited in vivo crosstalk between canonical and non-canonical Wnt signaling remains perplexing.
- Further research is needed to elucidate the in vivo interactions between these crucial signaling pathways.
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