TI - Inhibition of GSK3 by Wnt signalling--two contrasting models . AB - The key read-out of Wnt signalling is a change in the transcriptional profile of the cell , which is driven by beta-catenin . beta-catenin levels are normally kept low by a phosphorylation event that is mediated by glycogen synthase kinase 3 ( GSK3 , alpha - and beta-isoforms ) , which targets beta-catenin for ubiquitylation and proteasomal degradation . Wnt blocks this phosphorylation event , thereby allowing beta-catenin to accumulate and to co-activate transcription in the nucleus . Exactly how Wnt inhibits GSK3 activity towards beta-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 beta-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 beta-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 .