Abstract
Wnt/β-catenin signalling directs fundamental processes during metazoan development and can be aberrantly activated in cancer. Wnt stimulation induces the recruitment of the scaffold protein Axin from an inhibitory destruction complex to a stimulatory signalosome. Here we analyse the early effects of Wnt on Axin and find that the ADP-ribose polymerase Tankyrase (Tnks)—known to target Axin for proteolysis—regulates Axin's rapid transition following Wnt stimulation. We demonstrate that the pool of ADP-ribosylated Axin, which is degraded under basal conditions, increases immediately following Wnt stimulation in both Drosophila and human cells. ADP-ribosylation of Axin enhances its interaction with the Wnt co-receptor LRP6, an essential step in signalosome assembly. We suggest that in addition to controlling Axin levels, Tnks-dependent ADP-ribosylation promotes the reprogramming of Axin following Wnt stimulation; and propose that Tnks inhibition blocks Wnt signalling not only by increasing destruction complex activity, but also by impeding signalosome assembly.
Highlights
Wnt/b-catenin signalling directs fundamental processes during metazoan development and can be aberrantly activated in cancer
Two multimeric protein complexes with opposing functions—the cytoplasmic destruction complex and the plasma membraneassociated signalosome—control the stability of the transcriptional co-factor b-catenin to coordinate the state of Wnt pathway activation
In the absence of Wnt stimulation, b-catenin is targeted for proteasomal degradation by the destruction complex, which includes the two tumour suppressors: Axin and Adenomatous polyposis coli (APC), and two kinases: casein kinase 1a (CK1a) and glycogen synthase kinase 3 (GSK3)[3,4,5,6]
Summary
Wnt/b-catenin signalling directs fundamental processes during metazoan development and can be aberrantly activated in cancer. We suggest that in addition to controlling Axin levels, Tnks-dependent ADP-ribosylation promotes the reprogramming of Axin following Wnt stimulation; and propose that Tnks inhibition blocks Wnt signalling by increasing destruction complex activity, and by impeding signalosome assembly. Following Wnt exposure, the rapid association of phospho-Axin with phospho-LRP6 (refs 7,12,14) triggers Axin dephosphorylation, inducing a conformational change that inhibits Axin’s interaction with both the destruction and signalosome complexes[14,17,18]. Whereas the rapid switch in Axin function following Wnt stimulation is essential for the activation of signalling, the underlying mechanisms remain uncertain During investigation of this critical process, we have discovered an unanticipated role for the ADP-ribose polymerase Tankyrase (Tnks) in the reprogramming of Axin activity following Wnt exposure. Tnks targets Axin for proteolysis independently of Wnt stimulation, and promotes Axin’s central role in Wnt pathway activation, which may be relevant to the contextdependent activation of Wnt signalling and the treatment of Wnt-driven cancers with Tnks inhibitors
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