PMID:14992718

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Tewari, M, Hu, PJ, Ahn, JS, Ayivi-Guedehoussou, N, Vidalain, PO, Li, S, Milstein, S, Armstrong, CM, Boxem, M, Butler, MD, Busiguina, S, Rual, JF, Ibarrola, N, Chaklos, ST, Bertin, N, Vaglio, P, Edgley, ML, King, KV, Albert, PS, Vandenhaute, J, Pandey, A, Riddle, DL, Ruvkun, G and Vidal, M (2004) Systematic interactome mapping and genetic perturbation analysis of a C. elegans TGF-beta signaling network.Mol. Cell 13:469-82

To initiate a system-level analysis of C. elegans DAF-7/TGF-beta signaling, we combined interactome mapping with single and double genetic perturbations. Yeast two-hybrid (Y2H) screens starting with known DAF-7/TGF-beta 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-beta pathway mutant animals, identified nine DAF-7/TGF-beta 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-beta signaling. Our results reveal substantial molecular complexity in DAF-7/TGF-beta signal transduction. Integrating interactome maps with systematic genetic perturbations may be useful for developing a systems biology approach to this and other signaling modules.

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