Jade-1 inhibits Wnt signalling by ubiquitylating β-catenin and mediates Wnt pathway inhibition by pVHL

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Abstract
The tumour suppressor VHL is known to stabilize the ubiquitin ligase Jade-1. Jade-1 targets both phosphorylated and unphosphorylated -catenin, thereby linking VHL function directly to inhibition of Wnt signalling. The von Hippel–Lindau protein pVHL suppresses renal tumorigenesis in part by promoting the degradation of hypoxia-inducible HIF-α transcription factors1; additional mechanisms have been proposed2. pVHL also stabilizes the plant homeodomain protein Jade-1, which is a candidate renal tumour suppressor that may correlate with renal cancer risk3,4,5. Here we show that Jade-1 binds the oncoprotein β-catenin in Wnt-responsive fashion. Moreover, Jade-1 destabilizes wild-type β-catenin but not a cancer-causing form of β-catenin. Whereas the well-established β-catenin E3 ubiquitin ligase component β-TrCP ubiquitylates only phosphorylated β-catenin6, Jade-1 ubiquitylates both phosphorylated and non-phosphorylated β-catenin and therefore regulates canonical Wnt signalling in both Wnt-off and Wnt-on phases. Thus, the different characteristics of β-TrCP and Jade-1 may ensure optimal Wnt pathway regulation. Furthermore, pVHL downregulates β-catenin in a Jade-1-dependent manner and inhibits Wnt signalling, supporting a role for Jade-1 and Wnt signalling in renal tumorigenesis. The pVHL tumour suppressor and the Wnt tumorigenesis pathway are therefore directly linked through Jade-1.