Abstract
WNT regulates steady-state levels of β-catenin by partially inhibiting its phosphorylation.
Major finding: WNT regulates steady-state levels of β-catenin by partially inhibiting its phosphorylation.
Concept: Partial inhibition of degradation allows β-catenin to accumulate and maintain an elevated level.
Impact: Understanding the mode of β-catenin regulation may facilitate efforts to inhibit WNT signaling.
Hyperactive WNT signaling that culminates in nuclear β-catenin accumulation plays a key role in many cancers, but the exact β-catenin control mechanism is unclear. β-catenin is constantly synthesized, but in the absence of WNT ligand, the scaffold proteins AXIN1 and adenomatous polyposis coli (APC) establish an interaction between β-catenin and casein kinase 1α (CK1α) and glycogen synthase kinase (GSK3). As part of a destruction complex, these kinases sequentially phosphorylate β-catenin, creating a phosphodegron necessary for ubiquitination and subsequent proteasomal degradation. To determine the control point(s) at which WNT signaling acts to increase β-catenin levels, Hernandez and colleagues analyzed the kinetics of β-catenin steady-state levels in cultured cells. Continuous WNT stimulation sharply increased intracellular β-catenin levels but reduced the amount of GSK3-phosphorylated β-catenin within 15 to 30 minutes. When phosphorylation was restored to normal levels within 2 hours, β-catenin was maintained at a new higher steady-state level. However, β-catenin was degraded in both the presence and absence of WNT ligand, indicating that WNT only partially inhibits the destruction complex. Based on the laws of chemical kinetics, these findings were consistent with a mechanism in which WNT inhibits β-catenin degradation upstream or at the point of phosphorylation. Full recovery of phosphorylation and all downstream intermediates simply occurs as the system reestablishes equilibrium without a requirement for feedback. Similar analyses showed that WNT also blocked phosphorylation of β-catenin by CK1α, although it remains unclear whether the WNT signal acts on each kinase independently or on the destruction complex. These kinetic analyses reveal that the basic regulatory feature of the WNT pathway is partial inhibition of sequential phosphorylation events and suggest that compounds that affect the β-catenin degradation rate or modulate other control points of this simple system may be effective WNT inhibitors.
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