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lüll Application of an integrated physical and functional screening approach to identify inhibitors of the Wnt pathway Miller BW; Lau G; Grouios C; Mollica E; Barrios-Rodiles M; Liu Y; Datti A; Morris Q; Wrana JL; Attisano LMol Syst Biol 2009[]; 5 (ä): 315Large-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.|*Signal Transduction[MESH]|Adaptor Proteins, Signal Transducing[MESH]|Animals[MESH]|Axin Protein[MESH]|Calcium-Binding Proteins[MESH]|Carrier Proteins/metabolism[MESH]|Cell Line[MESH]|High-Throughput Screening Assays/*methods[MESH]|Humans[MESH]|Mice[MESH]|Models, Biological[MESH]|Protein Binding[MESH]|Protein Interaction Mapping[MESH]|RNA Interference[MESH]|Repressor Proteins/metabolism[MESH]|Ubiquitin-Conjugating Enzymes/metabolism[MESH]|Wnt Proteins/*antagonists & inhibitors[MESH] |