title: Jade-1 inhibits Wnt signalling by ubiquitylating beta-catenin and mediates Wnt pathway inhibition by pVHL.
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.
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Vipul C
authors.initials: VC
authors.lastname: Chitalia
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Foy
authors.forename: Markus M
authors.initials: MM
authors.lastname: Bachschmid
authors.forename: Liling
authors.initials: L
authors.lastname: Zeng
authors.forename: Maria V
authors.initials: MV
authors.lastname: Panchenko
authors.forename: Mina I
authors.initials: MI
authors.lastname: Zhou
authors.forename: Ajit
authors.initials: A
authors.lastname: Bharti
authors.forename: David C
authors.initials: DC
authors.lastname: Seldin
authors.forename: Stewart H
authors.initials: SH
authors.lastname: Lecker
authors.forename: Isabel
authors.initials: I
authors.lastname: Dominguez
authors.forename: Herbert T
authors.initials: HT
authors.lastname: Cohen
mesh_terms: D000818:Animals; D002460:Cell Line; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D054875:Ubiquitination; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014981:Xenopus; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; C469360:JADE1 protein, human; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D051794:Von Hippel-Lindau Tumor Suppressor Protein