title: Inhibitors of endocytosis prevent Wnt/Wingless signalling by reducing the level of basal β-catenin/Armadillo.
abstract: A key step in the canonical Wnt signalling pathway is the inhibition of GSK3β, which results in the accumulation of nuclear β-catenin (also known as CTNNB1), and hence regulation of target genes. Evidence suggests that endocytosis is required for signalling, yet its role and the molecular understanding remains unclear. A recent and controversial model suggests that endocytosis contributes to Wnt signalling by causing the sequestration of the ligand-receptor complex, including LRP6 and GSK3 to multivesicular bodies (MVBs), thus preventing GSK3β from accessing β-catenin. Here, we use specific inhibitors (Dynasore and Dyngo-4a) to confirm the essential role of endocytosis in Wnt/Wingless signalling in human and Drosophila cells. However, we find no evidence that, in Drosophila cells or wing imaginal discs, LRP6/Arrow traffics to MVBs or that MVBs are required for Wnt/Wingless signalling. Moreover, we show that activation of signalling through chemical blockade of GSK3β is prevented by endocytosis inhibitors, suggesting that endocytosis impacts on Wnt/Wingless signalling downstream of the ligand-receptor complex. We propose that, through an unknown mechanism, endocytosis boosts the resting pool of β-catenin upon which GSK3β normally acts.
authors.affiliation: MRC's National Institute for Medical Research, The Ridgeway, Mill Hill, London NW71AA, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Gagliardi
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Hernandez
authors.affiliation: MRC's National Institute for Medical Research, The Ridgeway, Mill Hill, London NW71AA, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: McGough
authors.affiliation: MRC's National Institute for Medical Research, The Ridgeway, Mill Hill, London NW71AA, UK jvincen@nimr.mrc.ac.uk.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vincent
mesh_terms: D000818:Animals; D001135:Armadillos; D004330:Drosophila; D004705:Endocytosis / Q000502:physiology*; D006801:Humans; D015398:Signal Transduction; D051155:Wnt1 Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051155:Wnt1 Protein; D051176:beta Catenin
keywords: Endocytosis; Signalling; Wnt; β-catenin