A novel nuclear protein, Chibby, binds to -catenin in competition with the transcription factor Tcf/Lef, thereby acting as an antagonist of the Wnt/Wingless signaling pathway.
The Wnt/Wingless signaling pathway is implicated in a wide array of developmental processes including segment polarity in Drosophila, as well as the development of some cancers. The oncoprotein -catenin (Armadillo (Arm) in Drosophila) is an integral component of Wnt/Wingless signaling cascade, and activates transcription by binding to the Tcf/Lef (T cell factor/lymphoid-enhancer factor) transcription factors. Chibby inhibits -catenin-mediated transcription by binding to its C-terminal Lef-binding domain.
Ken-Ichi Takemaru and colleagues have identified Chibby (Cby) in a screen for proteins that interact with the C-terminus of -catenin. Cby is predominantly a nuclear protein with several predicted nuclear localization signals and is expressed in several adult human tissues. The C-terminal half of Cby binds to a region of -catenin spanning Arm repeat 10 to the C-terminal transactivation domain. The interaction was confirmed in vivo using co-immunoprecipitation studies and the authors concluded that Cby is present constitutively in a complex with -catenin.
Overexpression of Cby repressed the transcriptional activation of the -catenin-dependent Tcf reporter TOPFLASH in a dose-dependent manner. Repression appears to be mediated through Cby and Lef-1 directly competing to bind with -catenin, which is Lef-1's co-activator. Inhibition of Cby in Drosophila by RNA interference causes a phenotype similar to that of embryos overexpressing wingless (wg) or the wg target genes engrailed (eng) or Ultrabithorax (Ubx). This leads to ectopic expression of transgenic flies carrying an UbxB-lacZ reporter, further confirming that cby functions as an antagonist of the wg pathway.
Epistasis analysis suggests that cby functions upstream of arm and downstream of wg and that the role of cby is to repress arm. As disruption in -catenin signaling is implicated in a wide range of cancers, these findings raise the possibility that the decreased Chibby expression observed in some human tumors may play a role in tumor formation.
Brenda Riley, Assistant Editor Signaling Gateway
References
Takemaru, Ken-Ichi Yamaguchi, Shinji Lee, Young Sik Zhang, Yang Carthew, Richard W. Moon, Randall T. Chibby, a nuclear -catenin-associated antagonist of the Wnt/Wingless pathway.
Nature, 422, 905–909
(2003) 10.1038/nature01570
-catenin in competition with the transcription factor Tcf/Lef, thereby acting as an antagonist of the Wnt/Wingless signaling pathway.
