title: Fringe proteins modulate Notch-ligand cis and trans interactions to specify signaling states.
abstract: The Notch signaling pathway consists of multiple types of receptors and ligands, whose interactions can be tuned by Fringe glycosyltransferases. A major challenge is to determine how these components control the specificity and directionality of Notch signaling in developmental contexts. Here, we analyzed same-cell (cis) Notch-ligand interactions for Notch1, Dll1, and Jag1, and their dependence on Fringe protein expression in mammalian cells. We found that Dll1 and Jag1 can cis-inhibit Notch1, and Fringe proteins modulate these interactions in a way that parallels their effects on trans interactions. Fringe similarly modulated Notch-ligand cis interactions during Drosophila development. Based on these and previously identified interactions, we show how the design of the Notch signaling pathway leads to a restricted repertoire of signaling states that promote heterotypic signaling between distinct cell types, providing insight into the design principles of the Notch signaling system, and the specific developmental process of Drosophila dorsal-ventral boundary formation.
authors.affiliation: Howard Hughes Medical Institute, California Institute of Technology, Pasadena, United States.
authors.forename: Lauren
authors.initials: L
authors.lastname: LeBon
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
authors.forename: Tom V
authors.initials: TV
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Tel Aviv University, Tel Aviv, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Sprinzak
authors.forename: Hamed
authors.initials: H
authors.lastname: Jafar-Nejad
authors.affiliation: Howard Hughes Medical Institute, California Institute of Technology, Pasadena, United States.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Elowitz
mesh_terms: D000818:Animals; D016466:CHO Cells; D002135:Calcium-Binding Proteins / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D014921:Wings, Animal / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D029721:Drosophila Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; C497759:N protein, Drosophila; D051880:Receptors, Notch; C000606278:Ser protein, Drosophila; D000072099:Serrate-Jagged Proteins; C064045:delta protein; D017351:N-Acetylglucosaminyltransferases; C090576:fng protein, Drosophila
keywords: D. melanogaster; cell signaling; developmental biology; developmental patterning; notch pathway; stem cells; systems biology