Jade-1 inhibits Wnt signalling by ubiquitylating beta-catenin and mediates Wnt pathway inhibition by pVHL.
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.
Chitalia
Vipul C
VC
Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Foy
Rebecca L
RL
Bachschmid
Markus M
MM
Zeng
Liling
L
Panchenko
Maria V
MV
Zhou
Mina I
MI
Bharti
Ajit
A
Seldin
David C
DC
Lecker
Stewart H
SH
Dominguez
Isabel
I
Cohen
Herbert T
HT
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*
D018398:Homeodomain Proteins; C469360:JADE1 protein, human; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D051794:Von Hippel-Lindau Tumor Suppressor Protein