Trends in Genetics
Volume 20, Issue 4, April 2004, Pages 177-181
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Rethinking WNT signaling

https://doi.org/10.1016/j.tig.2004.02.003Get rights and content

Abstract

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.

Section snippets

A central role for AXN phosphorylation and degradation

How DSH deactivates the destruction complex in cells that receive WNT signal is unclear. The focus of the research field has been on the involvement of GSK3β kinase, understandably, because it is the component with an easily identifiable function: it phosphorylates ARM. However, we have found that, in certain genetic backgrounds, ZW3 can be eliminated without blocking the ability of the cell to respond to the WNT signal. Under these conditions, ARM accumulates to uniform levels in all cells,

Does ARM function in the nucleus?

For AXN to function as an anchor, we must assume that the nuclear localization of ARM is essential for pathway activation. Consistent with this view, the final step in WNT signaling has long been thought to be the formation of a transactivating complex, in which the transcription factor TCF provides the specific DNA-binding activity and ARM provides the transcriptional activation. TCF is found predominantly in the nucleus but ARM is not: it is only after WNT activation that ARM is detectable in

Future directions

Although the WNT pathway has been a subject of intense study, since the discovery of WNT1 as the causal oncogene in mammary tumors [33], some vital questions remain unanswered. For example, what role does β-catenin play in the nucleus? Various functions have been proposed, including transactivation and chromatin remodeling [24]. The transcription factor most closely associated with WNT signaling is TCF, which is known to function in activation [34] and repression [35] of transcription. However,

Conclusion

We propose the following pathway for WNT activation. Extracellular WNT binds to FZ and this activated receptor–ligand complex recruits DSH and ARR. DSH and ARR localize AXN along with the other destruction-complex components to the membrane. At this point, DSH prevents the phosphorylation of AXN and ARR promotes the degradation of AXN, which rapidly disappears. The loss of AXN prevents the assembly of the destruction complex, enabling ARM levels to increase and also relieving the cytoplasmic

Acknowledgements

We are indebted to E. Lee for sharing his manuscript with us ahead of publication. We thank J. Goodliffe, A. Nouri and L. Manji for critical reading of the manuscript. This work was supported by the Howard Hughes Medical Institute and the National Institutes of Health grant P01CA41086 to E. Wieschaus. N. Tolwinski is supported by a New Jersey Commission of Cancer Research predoctoral fellowship.

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