Kinetic Responses of β-Catenin Specify the Sites of Wnt Control

Dissecting Wnt Signaling The Wnt signaling pathway plays a key role in regulating a broad range of functions from development to cancer. But a precise understanding of how Wnt proteins act through their receptors (Frizzled proteins) has been elusive. By paring the system down to its core reactions and performing kinetic analysis in cultured cells, Hernández et al. (p. 1337, published online 8 November) were able to deduce the mechanism of Wnt action without invoking any previous assumptions. Such quantitative analysis of mass balance may offer a way to identify essential control points in other complicated signaling systems, and thus help define targets for therapeutic intervention. Reducing the rate of phosphorylation of β-catenin leads to an increase in the steady-state level of the unmodified form. Despite more than 30 years of work on the Wnt signaling pathway, the basic mechanism of how the extracellular Wnt signal increases the intracellular concentration of β-catenin is still contentious. Circumventing much of the detailed biochemistry, we used basic principles of chemical kinetics coupled with quantitative measurements to define the reactions on β-catenin directly affected by the Wnt signal. We conclude that the core signal transduction mechanism is relatively simple, with only two regulated phosphorylation steps. Their partial inhibition gives rise to the full dynamics of the response and subsequently maintains a steady state in which the concentration of β-catenin is increased.