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J Cell Sci. 2014 Nov 15;127(Pt 22):4918-26. doi: 10.1242/jcs.155424. Epub 2014 Sep 18.

Inhibitors of endocytosis prevent Wnt/Wingless signalling by reducing the level of basal β-catenin/Armadillo.

Author information

1
MRC's National Institute for Medical Research, The Ridgeway, Mill Hill, London NW71AA, UK.
2
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
3
MRC's National Institute for Medical Research, The Ridgeway, Mill Hill, London NW71AA, UK jvincen@nimr.mrc.ac.uk.

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.

KEYWORDS:

Endocytosis; Signalling; Wnt; β-catenin

PMID:
25236598
PMCID:
PMC4231306
DOI:
10.1242/jcs.155424
[Indexed for MEDLINE]
Free PMC Article

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