The PDZ protein Canoe/AF-6 links Ras-MAPK, Notch and Wingless/Wnt signaling pathways by directly interacting with Ras, Notch and Dishevelled.
Over the past few years, it has become increasingly apparent that signal transduction pathways are not merely linear cascades; they are organized into complex signaling networks that require high levels of regulation to generate precise and unique cell responses. However, the underlying regulatory mechanisms by which signaling pathways cross-communicate remain poorly understood. Here we show that the Ras-binding protein Canoe (Cno)/AF-6, a PDZ protein normally associated with cellular junctions, is a key modulator of Wingless (Wg)/Wnt, Ras-Mitogen Activated Protein Kinase (MAPK) and Notch (N) signaling pathways cross-communication. Our data show a repressive effect of Cno/AF-6 on these three signaling pathways through physical interactions with Ras, N and the cytoplasmic protein Dishevelled (Dsh), a key Wg effector. We propose a model in which Cno, through those interactions, actively coordinates, at the membrane level, Ras-MAPK, N and Wg signaling pathways during progenitor specification.
Carmena
Ana
A
Program in Developmental Biology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Instituto de Neurosciencias de Alicante, Consejo Superior de Investigaciones Científicas/University Miguel Hernandez, Unidad de Neurobiología del Desarrollo, Alicante, Spain. acarmen@umh.es
Speicher
Stephan
S
Baylies
Mary
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D000072261:Dishevelled Proteins; D004330:Drosophila / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D017344:Genes, Insect; D020935:MAP Kinase Signaling System; D008648:Mesoderm / Q000196:embryology / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; C497759:N protein, Drosophila; D010750:Phosphoproteins; D051880:Receptors, Notch; D051153:Wnt Proteins; D051155:Wnt1 Protein; C092747:cno protein, Drosophila; C000606588:dsh protein, Drosophila; C074622:wg protein, Drosophila; D018631:ras Proteins