期刊
JOURNAL OF CELL SCIENCE
卷 127, 期 22, 页码 4918-4926出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.155424
关键词
beta-catenin; Wnt; Endocytosis; Signalling
类别
资金
- Medical Research Council [U117584268]
- European Union (European Research Council) [WNTEXPORT
- 294523]
- Wellcome Trust [31032011145326]
- National Institutes of Health [5R01HD073104-02]
A key step in the canonical Wnt signalling pathway is the inhibition of GSK3 beta, which results in the accumulation of nuclear beta-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 GSK3 beta from accessing beta-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 GSK3 beta 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 beta-catenin upon which GSK3 beta normally acts.
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