Jade-1 inhibits Wnt signalling by ubiquitylating β-catenin and mediates Wnt pathway inhibition by pVHL
Jade-1 inhibits Wnt signalling by ubiquitylating b-catenin and mediates Wnt pathway inhibition by pVHL
Chitalia, V. C. et al., Nat. Cell Biol. 10: 1208-1216 (2008)
Speaker: Shiao-Chi Chang (張筱琦) Time: 14:00-15:00, Feb. 25, 2009
Commentator: Hsiao-Sheng Liu (劉校生老師) Place: Room 601
Abstract
The von Hippel-Lindau protein (pVHL) has been characterized as a tumor suppressor in renal tumorigenesis. pVHL stabilizes the protein expression of Jade-1 (gene for apoptosis and differentiation in epithelia), a kidney-enriched transcription factor that promotes renal cancer cell apoptosis1. However, the role of Jade-1 in pVHL-mediated renal tumor suppression is yet to be elucidated. By using yeast two-hybrid screening of a human kidney cDNA library, the authors discovered that Jade-1 interacted with b-catenin, a central molecule of Wnt signaling2. Jade-1 bound the N-terminus of b-catenin, and phosphorylation of b-catenin at Ser33 by GSK3b was important for this interaction. Ectopic Jade-1 downregulated the expression of b-catenin in the cytosol and nucleus, and the cytosolic b-catenin was increased in Jade-1-knockdowned cells, indicating that Jade-1 may regulate the stability of b-catenin. Furthermore, the regulation of b-catenin by Jade-1 required GSK3b activity. Proteasome inhibitor MG132 blocked Jade-1-mediated dowregulation of b-catenin and caused the accumulation of ubiquitylated b-catenin. Jade-1 possesses two plant homeodomains (PHDs) that may express E3 ligase activity. Deletion of the OHDs abrogated Jade-1-mediated ubiquitylation of b-catenin and inhibitition of b-catenin/TCF transcription activity. Jade-1 suppressed Xwnt8 and b-catenin-induced ectopic axis formation in Xenopus laevis embryos, suggesting that Jade-1 is a negative regulator of Wnt signaling. Overexpression of pVHL downregulated b-catenin, and this effect was mitigated by Jade-1 knockdown. Taken together, pVHL inhibits the Wnt signaling by downregulating b-catenin through Jade-1, thus linking the pVHL tumor suppressor pathway and theWnt tumorigenesis signaling.
References
1. Zhou, M. I., Foy, R. L., Chitalia, V. C., Zhao, J., Panchenko, M. V., Wang, H., and Cohen, H. T. Jade-1, a candidate renal tumor suppressor that promotes apoptosis. Proc. Natl. Acad. Sci. USA 102: 11035-11040 (2005)
2. Huang, H. and He, X. Wnt/b-catenin signaling: new (and old) players and new insights. Curr. Opin. in Cell Biol. 20: 119-125 (2008)