Multivesicular GSK3 Sequestration upon Wnt Signaling Is Controlled by p120-Catenin/Cadherin Interaction with LRP5/6

Abstract

The Wnt canonical ligands elicit the activation of β-catenin transcriptional activity, a response dependent on, but not limited to, β-catenin stabilization through the inhibition of GSK3 activity. Two mechanisms have been proposed for this inhibition, one dependent on the binding and subsequent block of GSK3 to LRP5/6 Wnt coreceptor and another one on its sequestration into multivesicular bodies (MVBs). Here we report that internalization of the GSK3-containing Wnt-signalosome complex into MVBs is dependent on the dissociation of p120-catenin/cadherin from this complex. Disruption of cadherin-LRP5/6 interaction is controlled by cadherin phosphorylation and requires the previous separation of p120-catenin; thus, p120-catenin and cadherin mutants unable to dissociate from the complex block GSK3 sequestration into MVBs. These mutants substantially inhibit, but do not completely prevent, the β-catenin upregulation caused by Wnt3a. These results, besides elucidating how GSK3 is sequestered into MVBs, support this mechanism as cause of β-catenin stabilization by Wnt.

Maternal syntabulin is required for dorsal axis formation and is a germ plasm component in Xenopus

“…In Drosophila, Syntaxin1A was shown to be involved in the release of exosomes containing Wingless (Wg) and Wntless/Evenness Interrupted (Wls/ Evi), which are required for neuromuscular junction synapses ( Packard et al, 2002;. Syntabulin may provide a link between microtubules and membrane trafficking during the generation of the Wnt/β-Catenin signal (Taelman et al, 2010;Dobrowolski and De Robertis, 2011;Vinyoles et al, 2014). Further experiments will be required to understand the relationship between Syntabulin, a protein bound to microtubule motors, and the elusive dorsal determinants of the Xenopus egg.…”

“…When Wnt ligand binds to its receptors, the complex is internalized carrying with it Glycogen Synthase Kinase 3 (GSK3), which becomes sequestered from the cytosol into multivesicular bodies, resulting in the stabilization of proteins such as β-Catenin (Taelman et al, 2010;Dobrowolski and De Robertis, 2011). In addition to GSK3, other components of the activated LRP6 receptor complex such as Dvl-2, Axin and phospho-β-Catenin are also sequestered inside MVBs (Vinyoles et al, 2014). Given that Dvl-containing organelles are transported dorsally (Miller et al, 1999) and the connection between Wnt signaling and endosomal membrane trafficking, proteins that may link membrane vesicles to the microtubule machinery are of great interest.…”

Role of cell–cell adhesion complexes in embryonic stem cell biology

“…As there is growing evidence for an extensive cross-talk between p120ctn and b-catenin in several somatic cell types (Miller et al, 2013;Vinyoles et al, 2014), extended studies on the role of p120ctn in hESCs and other stem cell types might be worthwhile pursuing. For instance, the longest isoform of p120ctn can be phosphorylated by GSK3-b and targeted for proteasomal degradation through the same pathway as b-catenin degradation (Hong et al, 2010).…”

The MITF family of transcription factors: Role in endolysosomal biogenesis, Wnt signaling, and oncogenesis

“…This complex is then trafficked inside multivesicular bodies (MVBs) in an Endosomal Sorting Required for Transport (ESCRT)-dependent manner [6][7][8]. The sequestration of GSK3 and Axin inside MVBs is required for Wnt signaling, highlighting the importance of late endosomes as positive regulators of growth factor signaling [6,9].…”