Mapping the Disease Protein Interactome: Toward a Molecular Medicine GPS to Accelerate Drug and Biomarker Discovery

Abstract

Genomic approaches such as genome-wide association studies (GWAS), disease genome sequencing projects, and genome-wide expression profiling analyses, in conjunction with classical genetic approaches, can identify human genes that are altered in disease, thereby suggesting a role for the encoded protein (or RNA) in the establishment and/or progression of the disease. However, many technical difficulties challenge our ability to validate the role of these disease-associated genes and gene products. Moreover, many identified genes contain open reading frames (ORFs) that have yet to be annotated, that is, the function (or activity) of the encoded protein is unknown. As a result, translating the genomic information available in public databases into useful tools for understanding and curing disease is a very slow and inefficient process. To overcome these difficulties, we have developed a technology platform, termed the "molecular medicine GPS" (mm-GPS), which is aimed at defining high-quality maps of interaction networks involving disease proteins. These maps are used to identify network dysfunctions in disease cells or models and to develop molecular tools such as RNA interference (RNAi) and small-molecule inhibitors to further characterize the molecular basis of disease. In this article, I review our progress in producing high-quality maps of human protein interaction networks, and I describe how we used this information to identify new factors and pathways that regulate the RNA polymerase II transcription machinery. I also describe how we utilize the mm-GPS platform to guide more efficient efforts leading from disease-associated genes to protein interaction networks to smallmolecule inhibitors, and consequently, to accelerate drug and biomarker discovery. KeywordsProtein interaction networks; disease-associated genes; RNA polymerase II; transcription factors; biomarker and drug discovery; technology platform Interaction Networks As a New, Systems-Based "Descriptor" of Proteins CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptof the previously characterized interactors of a protein will inform on its function and localization within the cell. In addition, the network of interactors of a protein will often include regulatory factors that participate in modulating its activity. The value of this information, which must be validated using appropriate functional and biochemical assays, will increase with the quality of the interaction map.A number of experimental methods (see Figure 1 for Novel approaches, such as LUminescence-based Mammalian IntERactome mapping (LUMIER), 1 protein-fragment complementation assay (PCA), 20 and high throughput imaging of protein localization 29 have also been developed to help map protein-protein interactions in space and time in mammalian cells (see Figure 1 for a comparative description). Although these approaches have not been widely used to date, they will most certainly serve to enhance the confidence of protein-protein interactions by helping to desc...

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