Quantitative phosphoproteomics by mass spectrometry: Past, present, and future

Protein phosphorylation‐mediated signaling networks regulate much of the cellular response to external stimuli, and dysregulation in these networks has been linked to multiple disease states. Significant advancements have been made over the past decade to enable the analysis and quantification of cellular protein phosphorylation events, but comprehensive analysis of the phosphoproteome is still lacking, as is the ability to monitor signaling at the network level while comprehending the biological implications of each phosphorylation site. In this review we highlight many of the technological advances over the past decade and describe some of the latest applications of these tools to uncover signaling networks in a variety of biological settings. We finish with a concise discussion of the future of the field, including additional advances that are required to link protein phosphorylation analysis with biological insight.

[1]  D. Lauffenburger,et al.  Multiple reaction monitoring for robust quantitative proteomic analysis of cellular signaling networks , 2007, Proceedings of the National Academy of Sciences.

[2]  J. Rush,et al.  Immunoaffinity profiling of tyrosine phosphorylation in cancer cells , 2005, Nature Biotechnology.

[3]  J. Yates,et al.  Metabolic labeling of mammalian organisms with stable isotopes for quantitative proteomic analysis. , 2004, Analytical chemistry.

[4]  R. Aebersold,et al.  A systematic approach to the analysis of protein phosphorylation , 2001, Nature Biotechnology.

[5]  T. Pawson,et al.  Network medicine , 2008, FEBS letters.

[6]  Ruedi Aebersold,et al.  Comparative Evaluation of Current Peptide Production Platforms Used in Absolute Quantification in Proteomics*S , 2008, Molecular & Cellular Proteomics.

[7]  B. A. Ballif,et al.  ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage , 2007, Science.

[8]  Jeroen Krijgsveld,et al.  Metabolic labeling of C. elegans and D. melanogaster for quantitative proteomics , 2003, Nature Biotechnology.

[9]  M. Mann,et al.  Analysis of receptor signaling pathways by mass spectrometry: identification of vav-2 as a substrate of the epidermal and platelet-derived growth factor receptors. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[10]  M. Mann,et al.  Global, In Vivo, and Site-Specific Phosphorylation Dynamics in Signaling Networks , 2006, Cell.

[11]  A. Arnold,et al.  Regional differences in dosage compensation on the chicken Z chromosome , 2007, Genome Biology.

[12]  Steven P Gygi,et al.  Large-scale characterization of HeLa cell nuclear phosphoproteins. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Forest M. White,et al.  Modeling HER2 Effects on Cell Behavior from Mass Spectrometry Phosphotyrosine Data , 2006, PLoS Comput. Biol..

[14]  John E Hyde,et al.  Quantitative proteomics of the human malaria parasite Plasmodium falciparum and its application to studies of development and inhibition , 2004, Molecular microbiology.

[15]  S. Gygi,et al.  Quantitative analysis of complex protein mixtures using isotope-coded affinity tags , 1999, Nature Biotechnology.

[16]  R. Beynon,et al.  Multiplexed absolute quantification for proteomics using concatenated signature peptides encoded by QconCAT genes , 2006, Nature Protocols.

[17]  Steven P Gygi,et al.  Comparative evaluation of mass spectrometry platforms used in large-scale proteomics investigations , 2005, Nature Methods.

[18]  Adam A. Friedman,et al.  A functional RNAi screen for regulators of receptor tyrosine kinase and ERK signalling , 2006, Nature.

[19]  T. Pawson,et al.  Reading protein modifications with interaction domains , 2006, Nature Reviews Molecular Cell Biology.

[20]  M. Mann,et al.  Signaling Initiated by Overexpression of the Fibroblast Growth Factor Receptor-1 Investigated by Mass Spectrometry* , 2003, Molecular & Cellular Proteomics.

[21]  J. Shabanowitz,et al.  Phosphoproteome analysis by mass spectrometry and its application to Saccharomyces cerevisiae , 2002, Nature Biotechnology.

[22]  F. White,et al.  Uncovering Therapeutic Targets FOR Glioblastoma: A Systems Biology Approach , 2007, Cell cycle.

[23]  D. Lauffenburger,et al.  Time-resolved Mass Spectrometry of Tyrosine Phosphorylation Sites in the Epidermal Growth Factor Receptor Signaling Network Reveals Dynamic Modules*S , 2005, Molecular & Cellular Proteomics.

[24]  A. Pandey,et al.  A Novel Proteomic Approach for Specific Identification of Tyrosine Kinase Substrates Using [13C]Tyrosine* , 2004, Journal of Biological Chemistry.

[25]  L. Brill,et al.  Automated immobilized metal affinity chromatography/nano-liquid chromatography/electrospray ionization mass spectrometry platform for profiling protein phosphorylation sites. , 2005, Rapid communications in mass spectrometry : RCM.

[26]  Mark D'Ascenzo,et al.  8‐Plex quantitation of changes in cerebrospinal fluid protein expression in subjects undergoing intravenous immunoglobulin treatment for Alzheimer's disease , 2007, Proteomics.

[27]  R. Beynon,et al.  Multiplexed absolute quantification in proteomics using artificial QCAT proteins of concatenated signature peptides , 2005, Nature Methods.

[28]  Rune Matthiesen,et al.  Stable Isotope Labeling of Arabidopsis thaliana Cells and Quantitative Proteomics by Mass Spectrometry*S , 2005, Molecular & Cellular Proteomics.

[29]  H. Aburatani,et al.  Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer , 2007, Nature.

[30]  Ruedi Aebersold,et al.  Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry , 2005, Nature Methods.

[31]  F. White,et al.  Temporal Dynamics of Tyrosine Phosphorylation in Insulin Signaling , 2006, Diabetes.

[32]  Y. Yarden,et al.  Untangling the ErbB signalling network , 2001, Nature Reviews Molecular Cell Biology.

[33]  M. Yaffe,et al.  Signaling netwErks get the global treatment , 2007, Genome Biology.

[34]  Forest M White,et al.  Quantitative analysis of EGFRvIII cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma , 2007, Proceedings of the National Academy of Sciences.

[35]  B. Chait,et al.  Enrichment analysis of phosphorylated proteins as a tool for probing the phosphoproteome , 2001, Nature Biotechnology.

[36]  Blagoy Blagoev,et al.  Mechanism of Divergent Growth Factor Effects in Mesenchymal Stem Cell Differentiation , 2005, Science.

[37]  M. Mann,et al.  Stable Isotope Labeling by Amino Acids in Cell Culture, SILAC, as a Simple and Accurate Approach to Expression Proteomics* , 2002, Molecular & Cellular Proteomics.

[38]  David C Muddiman,et al.  Evaluation of a cleavable stable isotope labeled synthetic peptide for absolute protein quantification using LC-MS/MS. , 2004, Journal of proteome research.

[39]  Xiaohui S. Xie,et al.  A Mammalian Organelle Map by Protein Correlation Profiling , 2006, Cell.

[40]  M. Mann,et al.  Tyrosine Phosphoproteomics of Fibroblast Growth Factor Signaling , 2004, Journal of Biological Chemistry.

[41]  Bernhard Kuster,et al.  Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors , 2007, Nature Biotechnology.

[42]  M. Mann,et al.  A practical recipe for stable isotope labeling by amino acids in cell culture (SILAC) , 2006, Nature Protocols.

[43]  Ruedi Aebersold,et al.  An Integrated Chemical, Mass Spectrometric and Computational Strategy for (quantitative) Phosphoproteomics: Application to Drosophila Melanogaster Kc167 Cells{ , 2022 .

[44]  M. Mann,et al.  Higher-energy C-trap dissociation for peptide modification analysis , 2007, Nature Methods.

[45]  P. Roepstorff,et al.  Highly Selective Enrichment of Phosphorylated Peptides from Peptide Mixtures Using Titanium Dioxide Microcolumns* , 2005, Molecular & Cellular Proteomics.

[46]  Douglas A. Lauffenburger,et al.  networks Multiple reaction monitoring for robust quantitative proteomic analysis of cellular signaling , 2007 .

[47]  Keith L. Ligon,et al.  Coactivation of Receptor Tyrosine Kinases Affects the Response of Tumor Cells to Targeted Therapies , 2007, Science.

[48]  Steven P Gygi,et al.  Phosphoproteomic Analysis of the Developing Mouse Brain*S , 2004, Molecular & Cellular Proteomics.

[49]  Laura A. Sullivan,et al.  Global Survey of Phosphotyrosine Signaling Identifies Oncogenic Kinases in Lung Cancer , 2007, Cell.

[50]  M. Mann,et al.  Exponentially Modified Protein Abundance Index (emPAI) for Estimation of Absolute Protein Amount in Proteomics by the Number of Sequenced Peptides per Protein*S , 2005, Molecular & Cellular Proteomics.

[51]  T. Hunter,et al.  Signaling—2000 and Beyond , 2000, Cell.

[52]  Lewis Y. Geer,et al.  Analysis of phosphorylation sites on proteins from Saccharomyces cerevisiae by electron transfer dissociation (ETD) mass spectrometry , 2007, Proceedings of the National Academy of Sciences.

[53]  M. Mann,et al.  Quantitative Phosphoproteomics Applied to the Yeast Pheromone Signaling Pathway*S , 2005, Molecular & Cellular Proteomics.

[54]  Forest M White,et al.  Quantitative Analysis of Phosphotyrosine Signaling Networks Triggered by CD3 and CD28 Costimulation in Jurkat Cells1 , 2006, The Journal of Immunology.

[55]  Sampsa Hautaniemi,et al.  Effects of HER2 overexpression on cell signaling networks governing proliferation and migration , 2006, Molecular systems biology.

[56]  J. Porath,et al.  Isolation of phosphoproteins by immobilized metal (Fe3+) affinity chromatography. , 1986, Analytical biochemistry.

[57]  M. Mann,et al.  Temporal analysis of phosphotyrosine-dependent signaling networks by quantitative proteomics , 2004, Nature Biotechnology.

[58]  F. McLafferty,et al.  Electron capture dissociation for structural characterization of multiply charged protein cations. , 2000, Analytical chemistry.

[59]  D. J. Naylor,et al.  Proteome-wide Analysis of Chaperonin-Dependent Protein Folding in Escherichia coli , 2005, Cell.

[60]  Daniel B. Martin,et al.  Computational prediction of proteotypic peptides for quantitative proteomics , 2007, Nature Biotechnology.

[61]  J. Yates,et al.  Anion and cation mixed-bed ion exchange for enhanced multidimensional separations of peptides and phosphopeptides. , 2007, Analytical chemistry.

[62]  J. Shabanowitz,et al.  Peptide and protein sequence analysis by electron transfer dissociation mass spectrometry. , 2004, Proceedings of the National Academy of Sciences of the United States of America.