Jesse G. Zalatan, from the University of Washington, will deliver a seminar entitled, "Scaffold-Mediated Control of Competing Kinase Reactions in the Wnt Signaling Network." Hosted by Bobby Arora.
For more information on Jesse Zalatan, click here.
Abstract: GSK3β is a multifunctional kinase that phosphorylates β-catenin in the Wnt signaling network and acts on other protein targets in response to distinct cellular signals. GSK3β and β-catenin both bind the Axin scaffold protein, which could play a role in specifically regulating GSK3β signaling within the Wnt pathway. To determine how Axin regulates GSK3β activity, we biochemically reconstituted GSK3β-catalyzed reactions in vitro and quantitatively measured reaction rates in the presence and absence of Axin. Contrary to prior reports, we find that Axin produces a modest, 2-fold enhancement of the rate of phosphorylation of β-catenin. We can find conditions where Axin produces a substantially larger increase in observed rates, but this effect arises from an unexpected oligomerization event. At high concentrations of GSK3β, an inactive, oligomeric complex of GSK3β and β-catenin accumulates, and Axin prevents the formation of this inactive complex. No corresponding inactive complex forms in the GSK3β reaction with CREB, a non-Wnt pathway substrate, and Axin actually decreases the rate of CREB phosphorylation. These results prompt a reassessment of the molecular function of Axin in Wnt signaling. While Axin does preferentially enhance GSK3β activity towards β-catenin, this effect does not arise from tethering, and our revised mechanistic model does not fully explain how different GSK3β-dependent signaling events are insulated from each other in vivo. Other Wnt pathway proteins may have important and as-yet-unrecognized roles in regulating and modulating GSK3β activity towards β-catenin without affecting other GSK3β targets. More generally, the chaperone-like behavior of Axin reinforces an emerging trend that scaffold proteins are more complex than simple binding platforms and can regulate kinase activity through a diverse set of mechanisms.