Assembly of Wnt signalosomes by Dishevelled — ASN Events

Assembly of Wnt signalosomes by Dishevelled (#27)

Melissa Gammons 1 , Mariann Bienz 1
  1. MRC Laboratory of Molecular Biology, Cambridge, United Kingdom

Extracellular signals are often transduced by dynamic protein complexes (‘signalosomes’) that are assembled by cytoplasmic hub proteins following their recruitment to agonist-bound transmembrane receptors. One example is the Wnt signalosome, which is assembled by Dishevelled following its recruitment to the Frizzled seven-transmembrane receptors upon their binding to Wnt agonists. Wnt signalosome assembly by Dishevelled depends on dynamic and reversible head-to-tail polymerization by its DIX domain (1-3). This increases the local concentration of Dishevelled rapidly and dramatically, thus boosting its avidity for low-affinity binding partners, which empowers Dishevelled to interact with signaling effectors even if these are present at low cellular concentration (4). One key effector is Axin, which assembles a multiprotein complex via polymerization of its own DIX domain (‘Axin degradasome’) to destabilize b-catenin (5), a Wnt effector with pivotal roles in normal animal development and cancer (6). Upon Wnt stimulation, Dishevelled blocks the activity of the Axin degradasome, by co-polymerizing with Axin through heterotypic DIX-DIX interactions (7). We have recently discovered that the DEP domain of Dishevelled mediates signalosome assembly, by undergoing dimerization via ‘domain swapping’. This provides cross-linking of Dishevelled polymers, which illustrates a fundamental principle underlying signalosome formation (8). Both DIX-dependent polymerization and DEP-dependent dimerization require transient local concentration of Dishevelled. This could be provided by clathrin-coated pits to which Dishevelled may be recruited via binding to the Frizzled receptor following Wnt-dependent coupling between Frizzled and the LRP6 co-receptor (which itself is thought to be pre-localised in nascent pits). We shall discuss recent evidence that supports our model of clathrin-coated pits serving as locales for Wnt signal transduction.

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  2. Schwarz-Romond T, Fiedler M, Shibata N, Butler PGJ, Kikuchi A, Higuchi Y & Bienz M (2007) The DIX domain of Dishevelled triggers Wnt signaling by dynamic polymerization. Nature Struct Mol Biol 14, 484-492.
  3. Bilic J, Huang Y-L, Davidson G, Zimmermann T, Cruciat C-M, Bienz M & Niehrs C (2007) Wnt induces LRP6 signalosomes and promotes Dishevelled-dependent LRP6 phosphorylation. Science 316, 1619-1622.
  4. Bienz M (2014) Signalosome assembly by domains undergoing head-to-tail polymerization. Trend Biochem Sci 39, 487-495
  5. Mendoza-Topaz C, Mieszczanek J & Bienz M (2011) The Adenomatous polyposis coli tumour suppressor is essential for Axin complex assembly and function and opposes Axin’s interaction with Dishevelled. Open Biol 1, 110013.
  6. Bienz M & Clevers H (2000) Linking colorectal cancer to Wnt signaling. Cell 103, 311-320.
  7. Fiedler M, Mendoza-Topaz C, Rutherford TJ, Mieszczanek J & Bienz M (2011) Dishevelled interacts with the DIX domain polymerization interface of Axin to interfere with its function in down-regulating -catenin. Proc Natl Acad Sci USA 108, 1937-1942.
  8. Gammons M, Renko M, Johnson CM, Rutherford TJ & Bienz M (2016) Wnt signalosome assembly by DEP domain swapping of Dishevelled. Mol Cell 64, 92-104.