Abstract：
:The key read-out of Wnt signalling is a change in the transcriptional profile of the cell, which is driven by β-catenin. β-catenin levels are normally kept low by a phosphorylation event that is mediated by glycogen synthase kinase 3 (GSK3, α- and β-isoforms), which targets β-catenin for ubiquitylation and proteasomal degradation. Wnt blocks this phosphorylation event, thereby allowing β-catenin to accumulate and to co-activate transcription in the nucleus. Exactly how Wnt inhibits GSK3 activity towards β-catenin is unclear and has been the focus of intensive research. Recent studies on the role of conserved PPPSPxS motifs in the cytoplasmic tail of low-density lipoprotein receptor-related protein (LRP, isoforms 5 and 6) culminated in a biochemical model: Wnt induces the phosphorylation of LRP6 PPPSPxS motifs, which consequently access the catalytic pocket of GSK3 as pseudo-substrates, thus directly blocking its activity against β-catenin. A distinct cell-biological model was proposed more recently: Wnt proteins induce the uptake of GSK3 into multivesicular bodies (MVBs), an event that sequesters the enzyme away from newly synthesised β-catenin substrate in the cytoplasm, thus blocking its phosphorylation. This new model is based on intriguing observations but also challenges a body of existing evidence, so will require further experimental consolidation. We shall consider whether the two models apply to different modes of Wnt signaling: acute versus chronic.
journal_name
J Cell Scijournal_title
Journal of cell scienceauthors
Metcalfe C,Bienz Mdoi
10.1242/jcs.091991subject
Has Abstractpub_date
2011-11-01 00:00:00pages
3537-44issue
Pt 21eissn
0021-9533issn
1477-9137pii
124/21/3537journal_volume
124pub_type
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