24 December

Cross-talk between Wnt pathways increases signaling robustness

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The Korswagen group has found that cross-talk between the planar cell polarity pathway component Van Gogh (Vangl) and the canonical Wnt/beta-catenin pathway is an evolutionarily conserved mechanism that ensures robust specification of Wnt signaling responses. Their findings were published in PLOS Genetics on the 7th of December.

Wnt signaling plays a central role in development and adult tissue homeostasis, and is mediated through different evolutionarily conserved signaling pathways. The pathway that has been studied in most detail is the so-called canonical Wnt pathway, in which Wnt ligand binding to the receptors Frizzled and LRP6 leads to stabilization of beta-catenin and target gene activation. Other pathways, which are termed non-canonical Wnt pathways, act independently of beta-catenin and mostly function in controlling cell polarity and migration. In addition to their separate functions, there is evidence that the canonical and non-canonical Wnt pathways can also influence each other, but the function and molecular basis of this cross-talk is still poorly understood.

In this paper, Remco Mentink, Lorenzo Rella and colleagues used the C. elegans Q neuroblasts as a model system to study cross-talk between Wnt signaling pathways. Wnt signaling specifies the direction of migration of these neuroblasts, with posterior migration depending on canonical Wnt signaling and anterior migration on non-canonical Wnt signaling.

They found that the non-canonical Wnt pathway component Van Gogh (Vangl) negatively regulates canonical Wnt signaling, and that this cross-talk is necessary for robust specification of the Wnt dependent directional migration of the Q neuroblasts. In collaboration with the group of Vita Bryja at Masaryk University in Brno, Czech Republic, they found that the functional interaction between Vangl and canonical Wnt signaling is evolutionarily conserved in human cells.

Mechanistically, they show that Vangl acts through the intracellular signaling component Dishevelled (Dvl), a multifunctional protein that functions in both canonical and non-canonical Wnt signaling. The authors propose a model in which Vangl dampens canonical Wnt signaling by sequestering Dvl, thereby restricting the pool of Dvl that is available for pathway activation.

Deregulation of canonical Wnt signaling is one of the primary causes of colon cancer. Clinical studies have demonstrated that Vangl is frequently silenced by promoter hypermethylation in colon cancer cell lines and tumor samples. This study provides a mechanistic explanation for this tumor suppressive activity of Vangl.

Mentink, R.A., Rella, L., Radaszkiewicz, T.W., Gybel, T., Betist, M.C., Bryja, V., Korswagen, H.C. (2018) The planar cell polarity protein VANG-1/Vangl negatively regulates Wnt/beta-catenin signaling through a Dvl dependent mechanism. PLOS Genetics 14: e1007840.

Rik Korswagen is group leader at the Hubrecht Institute and professor of Molecular Developmental Genetics at Utrecht University.