Naked cuticle targets dishevelled to antagonize Wnt signal transduction.
In Drosophila embryos the protein Naked cuticle (Nkd) limits the effects of the Wnt signal Wingless (Wg) during early segmentation. nkd loss of function results in segment polarity defects and embryonic death, but how nkd affects Wnt signaling is unknown. Using ectopic expression, we find that Nkd affects, in a cell-autonomous manner, a transduction step between the Wnt signaling components Dishevelled (Dsh) and Zeste-white 3 kinase (Zw3). Zw3 is essential for repressing Wg target-gene transcription in the absence of a Wg signal, and the role of Wg is to relieve this inhibition. Our double-mutant analysis shows that, in contrast to Zw3, Nkd acts when the Wg pathway is active to restrain signal transduction. Yeast two hybrid and in vitro experiments indicate that Nkd directly binds to the basic-PDZ region of Dsh. Specially timed Nkd overexpression is capable of abolishing Dsh function in a distinct signaling pathway that controls planar-cell polarity. Our results suggest that Nkd acts directly through Dsh to limit Wg activity and thus determines how efficiently Wnt signals stabilize Armadillo (Arm)/beta-catenin and activate downstream genes.
Department of Developmental Biology, Howard Hughes Medical Institute, Beckman Center B300, Stanford University School of Medicine, Stanford, California 94305, USA.
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Rousset
J A
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Mack
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Wharton
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Axelrod
K M
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Cadigan
M P
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Fish
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Nusse
M P
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Scott
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051186:Armadillo Domain Proteins; D019521:Body Patterning; D019556:COS Cells; D003433:Crosses, Genetic; D000072261:Dishevelled Proteins; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins; D004591:Electrophoresis, Polyacrylamide Gel; D004843:Epistasis, Genetic; D018507:Gene Expression Regulation, Developmental; D038362:Glycogen Synthase Kinase 3; D049452:Green Fluorescent Proteins; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism*; D008164:Luminescent Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D016296:Mutagenesis; D009154:Mutation; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017956:Photoreceptor Cells, Invertebrate / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors; D020798:Two-Hybrid System Techniques; D051153:Wnt Proteins; D029961:Zebrafish Proteins
C495305:ARM protein, Drosophila; D048868:Adaptor Proteins, Signal Transducing; D051186:Armadillo Domain Proteins; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D019476:Insect Proteins; D008164:Luminescent Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C000606588:dsh protein, Drosophila; C405336:nkd protein, Drosophila; D049452:Green Fluorescent Proteins; D017346:Protein Serine-Threonine Kinases; C080335:Sgg protein, Drosophila; D038362:Glycogen Synthase Kinase 3