The development and clinical application of drugs that target intracellular signal-transduction pathways has profoundly changed the treatment of human cancers. Tools enabling complex pathway analysis, particularly those that can identify critical regulatory post-translational modifications, continue to facilitate discovery of novel targets for cancer therapeutics and provide insights into drug-resistance mechanisms.
At the Salk Institute’s “Protein Phosphorylation and Cell Signaling” meeting held recently in La Jolla, CA, academic and industry scientists described specific applications of these technologies, including the use of advanced databases to study disease-associated signaling networks and identification of specific mediators for analysis of signal transduction in animal models of human cancers.
Jon M. Kornhauser, Ph.D., scientific editor for Cell Signaling Technology’s PhosphoSitePlus™ described the application of PhosphoSitePlus (PSP) to the analysis of aberrant signaling through protein kinase networks in human disease states.
Pointing out that abnormal signaling has been implicated in the etiology of many diseases, particularly cancer, Dr. Kornhauser said that PhosphoSitePlus offers an online systems biology resource providing comprehensive information and tools for the study of protein post-translational modifications (PTMs). “PSP identifies over 70,000 sites from published literature, over 500 of which have been implicated (by correlation or causation) in specific diseases.”
PhosphoSitePlus aggregates information about the role of specific PTM sites in regulating biological processes. This aggregated data provides a resource for assembling protein-phosphorylation networks containing site-specific information, and for analysis of these networks to identify specific PTMs that may correlate with disease causation or progression.
Several types of protein interactions are curated in PSP including the protein kinases that catalyze phosphorylation of each site, and associations of specific phosphorylation sites and disease. Data in PSP can be accessed by a variety of flexible queries; for example, “treatment” searches in the user interface allow users to identify those modification sites that respond to specific drugs or ligands.
Dr. Kornhauser said that “PTM-specific interactions from PSP, combined with proteins implicated in disease pathways in other public database sources, can be used to assemble disease-centric signaling networks.”
According to Dr. Kornhauser, “PSP, unlike other pathway databases that are protein-centric, is PTM-specific; that is, it aggregates information about the role of specific modified residues in biological regulation. It is hoped that the data in PSP will allow researchers to identify specific modified residues that may serve as biomarkers of specific disease states, as prognostic markers for drug efficacy predictions, and potentially as therapeutic targets.”