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Systematic Interactome Mapping and Genetic Perturbation Analysis of a C. elegans TGF-β Signaling Network

2004; Elsevier BV; Volume: 13; Issue: 4 Linguagem: Inglês

10.1016/s1097-2765(04)00033-4

1097-4164

Muneesh Tewari, Patrick J Hu, Jin Sook Ahn, Nono Ayivi-Guedehoussou, Pierre‐Olivier Vidalain, Siming Li, Stuart Milstein, Chris M. Armstrong, Mike Boxem, Maurice D. Butler, S. Busiguina, Jean‐François Rual, Nieves Ibarrola, Sabrina T. Chaklos, Nicolas Bertin, Philippe Vaglio, Mark L. Edgley, Kevin V. King, Patrice S. Albert, Jean Vandenhaute, Akhilesh Pandey, Donald L Riddle, Gary Ruvkun, Marc Vidal,

Hormonal Regulation and Hypertension

To initiate a system-level analysis of C. elegans DAF-7/TGF-β signaling, we combined interactome mapping with single and double genetic perturbations. Yeast two-hybrid (Y2H) screens starting with known DAF-7/TGF-β pathway components defined a network of 71 interactions among 59 proteins. Coaffinity purification (co-AP) assays in mammalian cells confirmed the overall quality of this network. Systematic perturbations of the network using RNAi, both in wild-type and daf-7/TGF-β pathway mutant animals, identified nine DAF-7/TGF-β signaling modifiers, seven of which are conserved in humans. We show that one of these has functional homology to human SNO/SKI oncoproteins and that mutations at the corresponding genetic locus daf-5 confer defects in DAF-7/TGF-β signaling. Our results reveal substantial molecular complexity in DAF-7/TGF-β signal transduction. Integrating interactome maps with systematic genetic perturbations may be useful for developing a systems biology approach to this and other signaling modules. To initiate a system-level analysis of C. elegans DAF-7/TGF-β signaling, we combined interactome mapping with single and double genetic perturbations. Yeast two-hybrid (Y2H) screens starting with known DAF-7/TGF-β pathway components defined a network of 71 interactions among 59 proteins. Coaffinity purification (co-AP) assays in mammalian cells confirmed the overall quality of this network. Systematic perturbations of the network using RNAi, both in wild-type and daf-7/TGF-β pathway mutant animals, identified nine DAF-7/TGF-β signaling modifiers, seven of which are conserved in humans. We show that one of these has functional homology to human SNO/SKI oncoproteins and that mutations at the corresponding genetic locus daf-5 confer defects in DAF-7/TGF-β signaling. Our results reveal substantial molecular complexity in DAF-7/TGF-β signal transduction. Integrating interactome maps with systematic genetic perturbations may be useful for developing a systems biology approach to this and other signaling modules.