Bili inhibits Wnt/beta-catenin signaling by regulating the recruitment of axin to LRP6.
BACKGROUND
Insights into how the Frizzled/LRP6 receptor complex receives, transduces and terminates Wnt signals will enhance our understanding of the control of the Wnt/ss-catenin pathway.


RESULTS
In pursuit of such insights, we performed a genome-wide RNAi screen in Drosophila cells expressing an activated form of LRP6 and a beta-catenin-responsive reporter. This screen resulted in the identification of Bili, a Band4.1-domain containing protein, as a negative regulator of Wnt/beta-catenin signaling. We found that the expression of Bili in Drosophila embryos and larval imaginal discs significantly overlaps with the expression of Wingless (Wg), the Drosophila Wnt ortholog, which is consistent with a potential function for Bili in the Wg pathway. We then tested the functions of Bili in both invertebrate and vertebrate animal model systems. Loss-of-function studies in Drosophila and zebrafish embryos, as well as human cultured cells, demonstrate that Bili is an evolutionarily conserved antagonist of Wnt/beta-catenin signaling. Mechanistically, we found that Bili exerts its antagonistic effects by inhibiting the recruitment of AXIN to LRP6 required during pathway activation.


CONCLUSIONS
These studies identify Bili as an evolutionarily conserved negative regulator of the Wnt/beta-catenin pathway.
Kategaya
Lorna S
LS
Department of Pharmacology, Howard Hughes Medical Institute (HHMI), University of Washington School of Medicine and Institute for Stem Cell and Regenerative Medicine, Seattle, WA, USA.
Changkakoty
Binita
B
Biechele
Travis
T
Conrad
William H
WH
Kaykas
Ajamete
A
Dasgupta
Ramanuj
R
Moon
Randall T
RT
D000818:Animals; D060466:Axin Protein; D001483:Base Sequence; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D017931:DNA Primers; D006801:Humans; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008565:Membrane Proteins / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D011973:Receptors, LDL / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D060466:Axin Protein; D003598:Cytoskeletal Proteins; D017931:DNA Primers; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008565:Membrane Proteins; D011973:Receptors, LDL; D012097:Repressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C028841:erythrocyte membrane band 4.1 protein