Mapping in vivo signal transduction defects by phosphoproteomics

Abnormal protein phosphorylation is implicated in a variety of diseases, but until recently the complexity of tissue material, technical limitations, and the substantial volume of required data processing did not allow large-scale phosphoproteomic analysis of patient material, despite tremendous progress in developing mass spectrometry technologies. Phosphoproteomic approaches were primarily developed using model systems such as transformed cell lines, but technological advances in proteomics now make it feasible to analyze thousands of phosphorylation sites in a quantitative manner in patient materials or complex animal and cellular model systems to identify signaling abnormalities. This review summarizes very recent phosphoproteomic studies on complex tissue material, including tissue samples in biobanks, to complement recent reviews that focus primarily on technical advances in instrumentation and methods. Several successful examples reviewed here suggest it is now possible to apply phosphoproteomic techniques to address more challenging medical questions such as mapping within patient samples signal transduction defects that are relevant for diagnosis and individualized treatment development.