Journal
MOLECULAR CELL
Volume 13, Issue 4, Pages 469-482Publisher
CELL PRESS
DOI: 10.1016/S1097-2765(04)00033-4
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Funding
- NCI NIH HHS [7R33CA] Funding Source: Medline
- NHGRI NIH HHS [5R01HG01715-02] Funding Source: Medline
- NIA NIH HHS [K08-AG21613] Funding Source: Medline
- NIDDK NIH HHS [K08-DK62884] Funding Source: Medline
- NIGMS NIH HHS [GM60151] Funding Source: Medline
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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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