Journal
MOLECULAR SYSTEMS BIOLOGY
Volume 5, Issue -, Pages -Publisher
WILEY
DOI: 10.1038/msb.2009.72
Keywords
cancer biology; signal transduction; systems biology
Categories
Funding
- Canadian Institutes of Health Research [77690]
- Canadian Cancer Society
- Genome Canada through the Ontario Genomics Institute
- US NIH [R01HG001715]
- Ontario Research Fund
- Natural Sciences and Engineering Research Council
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Large-scale proteomic approaches have been used to study signaling pathways. However, identification of biologically relevant hits from a single screen remains challenging due to limitations inherent in each individual approach. To overcome these limitations, we implemented an integrated, multi-dimensional approach and used it to identify Wnt pathway modulators. The LUMIER protein-protein interaction mapping method was used in conjunction with two functional screens that examined the effect of overexpression and siRNA-mediated gene knockdown on Wnt signaling. Meta-analysis of the three data sets yielded a combined pathway score (CPS) for each tested component, a value reflecting the likelihood that an individual protein is a Wnt pathway regulator. We characterized the role of two proteins with high CPSs, Ube2m and Nkd1. We show that Ube2m interacts with and modulates beta-catenin stability, and that the antagonistic effect of Nkd1 on Wnt signaling requires interaction with Axin, itself a negative pathway regulator. Thus, integrated physical and functional mapping in mammalian cells can identify signaling components with high confidence and provides unanticipated insights into pathway regulators. Molecular Systems Biology 5; 315; published online 13 October 2009; doi:10.1038/msb.2009.72
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