Quantitative analysis of cell signaling and drug action via mass spectrometry-based systems level phosphoproteomics.
Protein phosphorylation is a primary form of information transfer in cell signaling pathways and plays a crucial role in regulating biological responses. Aberrant phosphorylation has been implicated in a number of diseases, and kinases and phosphatases, the cellular enzymes that control dynamic phosphorylation events, present attractive therapeutic targets. However, the innate complexity of signaling networks has presented many challenges to therapeutic target selection and successful drug development. Approaches in phosphoproteomics can contribute functional, systems-level datasets across signaling networks that can provide insight into suitable drug targets, more broadly profile compound activities, and identify key biomarkers to assess clinical outcomes. Advances in MS-based phosphoproteomics efforts now provide the ability to quantitate phosphorylation with throughput and sensitivity to sample a significant portion of the phosphoproteome in clinically relevant systems. This review will discuss recent work and examples of application data that demonstrate the utility of MS, with a particular focus on the use of quantitative phosphoproteomics and phosphotyrosine-directed signaling analyses to provide robust measurement for functional biological interpretation of drug action on signaling and phenotypic outcomes.
Tedford
Nathan C
NC
Epitome Biosystems Inc, Waltham, MA, USA. ntedford@mit.edu
Hall
Amy B
AB
Graham
James R
JR
Murphy
Cheryl E
CE
Gordon
Neal F
NF
Radding
Jeffrey A
JA
D000818:Animals; D002460:Cell Line; D055808:Drug Discovery; D006801:Humans; D013058:Mass Spectrometry; D010750:Phosphoproteins / Q000032:analysis*; D040901:Proteomics / Q000379:methods*; D015398:Signal Transduction
D010750:Phosphoproteins