Research ArticleDevelopmental Biology

Huwe1-Mediated Ubiquitylation of Dishevelled Defines a Negative Feedback Loop in the Wnt Signaling Pathway

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Science Signaling  18 Mar 2014:
Vol. 7, Issue 317, pp. ra26
DOI: 10.1126/scisignal.2004985

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UbiqWNTin Feedback

The Wnt/β-catenin pathway directs the migration of the Q neuroblasts in Caenorhabditis elegans. In response to Wnt pathway activation, Dishevelled (Dvl) is activated and the degradation of β-catenin is prevented. Dvl activity is regulated by phosphorylation and ubiquitylation. Using an RNA interference screen targeting ubiquitin ligases and deubiquitylating enzymes, de Groot et al. identified the E3 ubiquitin ligase EEL-1 as a Wnt signaling inhibitor that affected Q neuroblast migration. Knockdown of the EEL-1 homolog Huwe1 in human embryonic kidney 293T cells enhanced the activity of the Wnt/β-catenin transcriptional pathway. Huwe1 interacted and colocalized with Dvl. Huwe1 promoted the ubiquitylation of the DIX domain in Dvl and inhibited Dvl multimerization. Thus, Huwe1 functions as an evolutionarily conserved feedback inhibitor of Wnt signaling.

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