Recent research on the WNT signaling pathway warrants a reassessment of the basic mechanism that transmits signal from the membrane-bound receptor to the nucleus. This article incorporates these findings into a revised model for pathway activation. We propose that the control of Axin stability, rather than the control of ZW3 phosphorylation of the Armadillo protein, is the key step in signaling. Axin degradation is controlled by a stabilizing effect of ZW3-dependent phosphorylation, and a destabilizing effect of active Arrow. Removing Axin enables Armadillo to accumulate and re-localize to the nucleus. We argue that nuclear localization of Armadillo is required for transcriptional pathway activity. Finally, we speculate on the effects this revision will have on the major questions facing the WNT field of research.
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