GSK3: a multifaceted kinase in Wnt signaling

Abstract

GSK3 is one of the few signaling mediators that play central roles in a diverse range of signaling pathways, including those activated by Wnts, hedgehog, growth factors, cytokines, and G protein-coupled ligands. Although the inhibition of GSK3-mediated beta-catenin phosphorylation is known to be the key event in Wnt-beta-catenin signaling, the mechanisms that underlie this event remain incompletely understood. The recent demonstration of GSK3 involvement in Wnt receptor phosphorylation illustrates the multifaceted roles that GSK3 plays in Wnt-beta-catenin signaling. In this review, we will summarize these recent results and offer explanations, hypotheses, and models to reconcile some of these observations.

Figure 1. Schematic representation of simplified canonical Wnt signaling pathways

There are generally two pools of β-catenin in cells. One pool is associated with cadherins, whereas the other is degraded in the absence of Wnt by the β-catenin destruction complex. Wnt binds two cell surface receptors (LRP5/6 and FZD) and leads to phosphorylation at least of Thr-1479 by CKIγ, Ser-1490 by GSK3, and Thr-1493 by yet to be identified CKs on LRP6. These phosphorylation events are required for AXIN recruitment and β-catenin stabilization. Stabilized β-catenin enters the nucleus and activates gene transcription activation. Two of the Wnt antagonists, Dickkopf (DKK) and soluble frizzled-related protein (sFRP), are also shown.

Figure 2. Three major models for the regulation of LRP5/6 phosphorylation

In the direct inhibition model, GSK3 might be directly inhibited by phosphorylated PPP(S/T)P motifs. GSK3 might be recruited in a manner depending on AXIN, which might be recruited by Wnt via FZD and DVL. In the signalosome model, Wnt induces clustering of LRP6, leading to its phosphorylation by CKIγ and subsequently by GSK3 and recruitment of AXIN. PIP2, whose production is stimulated by Wnt via FZD and DVL, is required for the signalosome formation. GPCRs such as PTH1R might interact with LRP6 and regulates LRP6 phosphorylation and AXIN recruitment. Proteins that were identified recently for promoting or inhibiting LRP6 phosphorylation are listed.

Figure 3. Hypothetical depiction of three GSK pools and their possible involvement in regulation of diverse signaling pathways

Three pools of GSK3 are hypothesized to exist. One pool is associated with AXIN and probably regulated by LRP5/6. Another pool is regulated by phosphorylation at Ser9 or Ser-27 by the PI3K-AKT pathway. Additionally, there might be an AXIN-independent pool of GSK3, which is also regulated by Wnt. However, the mechanisms by which this pool would be regulated are not clear.