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Wnt Signalosome Assembly by DEP Domain Swapping of Dishevelled.

Gammons MV, Renko M, Johnson CM, Rutherford TJ, Bienz M
Mol Cell 64 92-104 (2016)
Related entries: 5suy, 5suz

Cited: 85 times
EuropePMC logo PMID: 27692984

Abstract

Extracellular signals are often transduced by dynamic signaling complexes ("signalosomes") assembled by oligomerizing hub proteins following their recruitment to signal-activated transmembrane receptors. A paradigm is the Wnt signalosome, which is assembled by Dishevelled via reversible head-to-tail polymerization by its DIX domain. Its activity causes stabilization of β-catenin, a Wnt effector with pivotal roles in animal development and cancer. How Wnt triggers signalosome assembly is unknown. Here, we use structural analysis, as well as biophysical and cell-based assays, to show that the DEP domain of Dishevelled undergoes a conformational switch, from monomeric to swapped dimer, to trigger DIX-dependent polymerization and signaling to β-catenin. This occurs in two steps: binding of monomeric DEP to Frizzled followed by DEP domain swapping triggered by its high local concentration upon Wnt-induced recruitment into clathrin-coated pits. DEP domain swapping confers directional bias on signaling, and the dimerization provides cross-linking between Dishevelled polymers, illustrating a key principle underlying signalosome formation.

Reviews - 5lnp mentioned but not cited (1)

  1. Wnt signaling in triple-negative breast cancer. Pohl SG, Brook N, Agostino M, Arfuso F, Kumar AP, Dharmarajan A. Oncogenesis 6 e310 (2017)


Reviews citing this publication (29)

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Articles citing this publication (55)

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