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

Nat Cell Biol. 2008 Oct;10(10):1208-16. doi: 10.1038/ncb1781. Epub 2008 Sep 21.

Abstract

The von Hippel-Lindau protein pVHL suppresses renal tumorigenesis in part by promoting the degradation of hypoxia-inducible HIF-alpha transcription factors; additional mechanisms have been proposed. pVHL also stabilizes the plant homeodomain protein Jade-1, which is a candidate renal tumour suppressor that may correlate with renal cancer risk. Here we show that Jade-1 binds the oncoprotein beta-catenin in Wnt-responsive fashion. Moreover, Jade-1 destabilizes wild-type beta-catenin but not a cancer-causing form of beta-catenin. Whereas the well-established beta-catenin E3 ubiquitin ligase component beta-TrCP ubiquitylates only phosphorylated beta-catenin, Jade-1 ubiquitylates both phosphorylated and non-phosphorylated beta-catenin and therefore regulates canonical Wnt signalling in both Wnt-off and Wnt-on phases. Thus, the different characteristics of beta-TrCP and Jade-1 may ensure optimal Wnt pathway regulation. Furthermore, pVHL downregulates beta-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Homeodomain Proteins / metabolism*
  • Humans
  • Protein Binding
  • Signal Transduction*
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitination*
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism*
  • Wnt Proteins / antagonists & inhibitors
  • Wnt Proteins / metabolism*
  • Xenopus
  • beta Catenin / metabolism*

Substances

  • Homeodomain Proteins
  • JADE1 protein, human
  • Tumor Suppressor Proteins
  • Wnt Proteins
  • beta Catenin
  • Von Hippel-Lindau Tumor Suppressor Protein