Toggling a conformational switch in Wnt/β-catenin signaling: regulation of Axin phosphorylation. The phosphorylation state of Axin controls its scaffold function in two Wnt pathway protein complexes - PubMed (original) (raw)

Review

Toggling a conformational switch in Wnt/β-catenin signaling: regulation of Axin phosphorylation. The phosphorylation state of Axin controls its scaffold function in two Wnt pathway protein complexes

Ofelia Tacchelly-Benites et al. Bioessays. 2013 Dec.

Abstract

The precise orchestration of two opposing protein complexes - one in the cytoplasm (β-catenin destruction complex) and the other at the plasma membrane (LRP6 signaling complex) - is critical for controlling levels of the transcriptional co-factor β-catenin, and subsequent activation of the Wnt/β-catenin signal transduction pathway. The Wnt pathway component Axin acts as an essential scaffold for the assembly of both complexes. How the β-catenin destruction and LRP6 signaling complexes are modulated following Wnt stimulation remains controversial. A recent study in Science by He and coworkers reveals an underlying logic for Wnt pathway control in which Axin phosphorylation toggles a switch between the active and inactive states. This mini-review focuses on this and two other recent studies that provide insight into the initial signaling events triggered by Wnt exposure. We emphasize regulation of the β-catenin destruction and LRP6 signaling complexes and propose a framework for future work in this area.

Keywords: Axin; LRP6 signaling complex; PP1; Wnt signal transduction; β-catenin destruction complex.

© 2013 WILEY Periodicals, Inc.

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Figures

Figure 1

Figure 1. Wnt/β-catenin Signaling

A) The β-catenin destruction complex. In the absence of Wnt stimulation, steady-state levels of β-catenin are maintained via its constitutive synthesis and proteolysis. The Axin scaffold facilitates the association of β-catenin, GSK3, CK1α , and APC. Phosphorylation of β-catenin by CK1α and GSK3 promotes its recognition by the E3 ubiquitin ligase β-TrCP, targeting β-catenin for proteasomal degradation. B) The LRP6 signaling complex. Wnt exposure induces formation of a receptor complex between Fz, LRP6, and Wnt, and recruitment of Dvl to Fz. Formation of this complex triggers phosphorylation of LRP6 by GSK3 and CK1, and subsequent recruitment of Axin and GSK3 to phospho-LRP6, which results in increased LRP6 phosphorylation. Formation of the LRP6 signaling complex results in inactivation of the destruction complex, leading to β-catenin stabilization, nuclear translocation, and a Wnt-specific transcriptional program.

Figure 2

Figure 2. The Axin conformation controls its scaffold function

Left. In the absence of Wnt, Axin is phosphorylated by GSK3 at the S497/500 sites, located within the central β-catenin binding domain (BCD). Axin phosphorylation results in an “open” conformation that promotes its interaction with β-catenin, targeting β-catenin for ubiquitin-dependent proteolysis. The open conformation also primes Axin for interaction with LRP6. GID: GSK3 interaction domain; DIX: Dishevelled interaction domain. Right. In the presence of Wnt, Axin is dephosphorylated by PP1 at the S497/500 sites. Following its dephosphorylation, the BCD of Axin associates with its carboxy-terminal DIX domain, resulting in a “closed” conformation. This intramolecular association prevents the interaction of Axin with both LRP6 and β-catenin, thereby inactivating Axin.

Figure 3

Figure 3. The Axin phosphorylation/dephosphorylation cycle

Top left, in the absence of Wnt. Axin is phosphorylated by GSK3, maintained in an open conformation, engaged in the destruction complex, and primed for interaction with LRP6. Top right, Phase I following Wnt exposure. LRP6 undergoes phosphorylation. Phospho-Axin is recruited from the destruction complex to the LRP6 signaling complex through its interaction with phospho-LRP6. Bottom right, Phase II following Wnt exposure. The LRP6 signaling complex inhibits GSK3, thereby tipping the balance towards Axin dephosphorylation by PP1. Bottom left, Phase III following Wnt exposure. Dephosphorylation of Axin by PP1 results in a closed conformation, thereby disengaging Axin from LRP6 and β-catenin. Phospho-LRP6 becomes free for additional rounds of engagement with phospho-Axin, leading to further dephosphorylation and inactivation of Axin. Dephosphorylated Axin is subsequently targeted for proteasomal degradation or recycled for destruction complex assembly.

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