Wnt signalling plays important roles during embryonic patterning and in tissue homeostasis, and mutations that affect the Wnt pathway are associated with cancer. Despite this, the exact way in which the Wnt pathway is regulated is still not fully understood. Now, Amy Bejsovec and colleagues uncover a novel regulator of Wnt signalling (). Previous studies have shown that the Drosophila RhoGEF Pebble (Pbl) might influence patterning mediated by Wingless (Wg), the primary fly Wnt. Following this, the authors show that both loss- and gain-of-function Drosophila pbl mutants exhibit defects that are consistent with a role for Pbl in negatively regulating the Wg pathway. Furthermore, both Pbl and ECT2, the human homologue of Pbl, downregulate Wnt reporter activity in cultured Drosophila and human cells, highlighting a role for ECT2 as a potential proto-oncogene. Finally, the researchers show that, unlike most negative regulators of the Wnt pathway, Pbl acts downstream of Armadillo/β-catenin and may act through Rho1 to negatively regulate Wnt/Wg signalling.
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