Receptor tyrosine kinase signaling: a view from quantitative proteomics.

Growth factor receptor signaling via receptor tyrosine kinases (RTKs) is one of the basic cellular communication principals found in all metazoans. Extracellular signals are transferred via membrane spanning receptors into the cytoplasm, reversible tyrosine phosphorylation being the hallmark of all RTKs. In recent years proteomic approaches have yielded detailed descriptions of cellular signaling events. Quantitative proteomics is able to characterize the exact position and strength of post-translational modifications (PTMs) providing essential information for understanding the molecular basis of signal transduction. Numerous new post-translational modification sites have been identified by quantitative mass spectrometry-based proteomics. In addition, plentiful new players in signal transduction have been identified underlining the complexity and the modular architecture of most signaling networks. In this review, we outline the principles of signal transduction via RTKs and highlight some of the new insights obtained from proteomic approaches such as protein microarrays and quantitative mass spectrometry.

[1]  M. Mann,et al.  Is Proteomics the New Genomics? , 2007, Cell.

[2]  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.

[3]  Yosef Yarden,et al.  Endocytosis of Receptor Tyrosine Kinases Is Driven by Monoubiquitylation, Not Polyubiquitylation* , 2003, Journal of Biological Chemistry.

[4]  A. Ullrich,et al.  The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling , 1992, Cell.

[5]  B. Kholodenko.  Cell-signalling dynamics in time and space , 2006, Nature Reviews Molecular Cell Biology.

[6]  G L Johnson,et al.  Organization and regulation of mitogen-activated protein kinase signaling pathways. , 1999, Current opinion in cell biology.

[7]  T. Pollard,et al.  Regulation of phospholipase C-gamma 1 by profilin and tyrosine phosphorylation. , 1991, Science.

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

[9]  J. Schlessinger,et al.  Activation of phospholipase Cγ by PI 3‐kinase‐induced PH domain‐mediated membrane targeting , 1998 .

[10]  T. Pawson,et al.  Signaling through scaffold, anchoring, and adaptor proteins. , 1997, Science.

[11]  B. Blagoev,et al.  Stable isotope labeling by amino acids in cell culture (SILAC). , 2008, Methods in molecular biology.

[12]  T. Pawson,et al.  Assembly of Cell Regulatory Systems Through Protein Interaction Domains , 2003, Science.

[13]  F. White.  Quantitative phosphoproteomic analysis of signaling network dynamics. , 2008, Current opinion in biotechnology.

[14]  Troels Z. Kristiansen,et al.  Cloning of a novel phosphotyrosine binding domain containing molecule, Odin, involved in signaling by receptor tyrosine kinases , 2002, Oncogene.

[15]  S. Gygi,et al.  Absolute quantification of proteins and phosphoproteins from cell lysates by tandem MS , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Blagoy Blagoev,et al.  A proteomics strategy to elucidate functional protein-protein interactions applied to EGF signaling , 2003, Nature Biotechnology.

[17]  J. Schlessinger,et al.  Cell Signaling by Receptor Tyrosine Kinases , 2000, Cell.

[18]  T. Hunter,et al.  Receptor protein-tyrosine kinases and their signal transduction pathways. , 1994, Annual review of cell biology.

[19]  M. Mann,et al.  Mass spectrometry–based proteomics turns quantitative , 2005, Nature chemical biology.

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

[21]  Sheila M. Thomas,et al.  Cellular functions regulated by Src family kinases. , 1997, Annual review of cell and developmental biology.

[22]  M. Snyder,et al.  Analyzing antibody specificity with whole proteome microarrays , 2003, Nature Biotechnology.

[23]  K. Resing,et al.  Comparison of Label-free Methods for Quantifying Human Proteins by Shotgun Proteomics*S , 2005, Molecular & Cellular Proteomics.

[24]  Lewis C. Cantley,et al.  The Role of Phosphoinositide 3-Kinase Lipid Products in Cell Function* , 1999, The Journal of Biological Chemistry.

[25]  A. Tari,et al.  GRB2: a pivotal protein in signal transduction. , 2001, Seminars in oncology.

[26]  M. Mann,et al.  Global and site-specific quantitative phosphoproteomics: principles and applications. , 2009, Annual review of pharmacology and toxicology.

[27]  Gordon B. Mills,et al.  Derailed endocytosis: an emerging feature of cancer , 2008, Nature Reviews Cancer.

[28]  Ivan Dikic,et al.  Negative receptor signalling. , 2003, Current opinion in cell biology.

[29]  D Cowburn,et al.  Modular peptide recognition domains in eukaryotic signaling. , 1997, Annual review of biophysics and biomolecular structure.

[30]  J. Schlessinger,et al.  Activation of phospholipase C gamma by PI 3-kinase-induced PH domain-mediated membrane targeting. , 1998, The EMBO journal.

[31]  N. Normanno,et al.  Epidermal growth factor-related peptides and their receptors in human malignancies. , 1995, Critical reviews in oncology/hematology.

[32]  Emanuel F. Petricoin,et al.  Laser Capture Microdissection and Protein Microarray Analysis of Human Non-small Cell Lung Cancer , 2008, Molecular & Cellular Proteomics.

[33]  Lukas N. Mueller,et al.  An assessment of software solutions for the analysis of mass spectrometry based quantitative proteomics data. , 2008, Journal of proteome research.

[34]  S. Harrison,et al.  Crystal structures of c-Src reveal features of its autoinhibitory mechanism. , 1999, Molecular cell.

[35]  Pier Paolo Di Fiore,et al.  Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation , 2003, Nature Cell Biology.

[36]  B. Kennedy,et al.  Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. , 1999, Science.

[37]  M. Czech,et al.  PIP2 and PIP3 Complex Roles at the Cell Surface , 2000, Cell.

[38]  S. Bowen,et al.  Constitutive phosphorylation of the epidermal growth factor receptor blocks mitogenic signal transduction. , 1991, The Journal of biological chemistry.

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

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

[41]  Richard D. Smith,et al.  Quantitative proteomic approaches for studying phosphotyrosine signaling , 2007, Expert review of proteomics.

[42]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.

[43]  S. Hubbard,et al.  Structural Basis for FGF Receptor Dimerization and Activation , 1999, Cell.

[44]  Xuejun Jiang,et al.  Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. , 2006, Molecular cell.

[45]  A. Zilberstein,et al.  PDGF stimulation of inositol phospholipid hydrolysis requires PLC-γ1 phosphorylation on tyrosine residues 783 and 1254 , 1991, Cell.

[46]  T. Hunter,et al.  Protein kinases and phosphatases: The Yin and Yang of protein phosphorylation and signaling , 1995, Cell.

[47]  Tony Hunter,et al.  Receptor signaling: When dimerization is not enough , 1999, Current Biology.

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

[49]  K. Parker,et al.  Multiplexed Protein Quantitation in Saccharomyces cerevisiae Using Amine-reactive Isobaric Tagging Reagents*S , 2004, Molecular & Cellular Proteomics.

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

[51]  Gavin MacBeath,et al.  A quantitative protein interaction network for the ErbB receptors using protein microarrays , 2006, Nature.

[52]  Matthias Mann,et al.  A Mass Spectrometry-based Proteomic Approach for Identification of Serine/Threonine-phosphorylated Proteins by Enrichment with Phospho-specific Antibodies , 2002, Molecular & Cellular Proteomics.

[53]  E. Wingender,et al.  Identification of dominant signaling pathways from proteomics expression data. , 2008, Journal of proteomics.

[54]  M. Yaffe.  Phosphotyrosine-binding domains in signal transduction , 2002, Nature Reviews Molecular Cell Biology.

[55]  M. Shibuya,et al.  A highly conserved tyrosine residue at codon 845 within the kinase domain is not required for the transforming activity of human epidermal growth factor receptor. , 1992, Biochemical and biophysical research communications.

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

[57]  Tony Pawson,et al.  Regulation and targets of receptor tyrosine kinases. , 2002, European journal of cancer.

[58]  M. Mann,et al.  Phosphotyrosine interactome of the ErbB-receptor kinase family , 2005, Molecular systems biology.

[59]  M. Kirschner,et al.  Stable isotope-free relative and absolute quantitation of protein phosphorylation stoichiometry by MS. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[60]  Blagoy Blagoev,et al.  Quantitative proteomic assessment of very early cellular signaling events , 2007, Nature Biotechnology.

[61]  M. Mann,et al.  4. Proteomic Analysis of Posttranslational Modifications , 2013 .

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

[63]  W. Fantl,et al.  Signalling by receptor tyrosine kinases. , 1993, Annual review of biochemistry.

[64]  Sebastian A. Wagner,et al.  Regulation of ubiquitin-binding proteins by monoubiquitination , 2006, Nature Cell Biology.

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

[66]  S. Gygi,et al.  Profiling of UV-induced ATM/ATR signaling pathways , 2007, Proceedings of the National Academy of Sciences.

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

[68]  C. Kahn,et al.  A cascade of tyrosine autophosphorylation in the beta-subunit activates the phosphotransferase of the insulin receptor. , 1988, The Journal of biological chemistry.

[69]  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.

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

[71]  Matthias Mann,et al.  High confidence determination of specific protein-protein interactions using quantitative mass spectrometry. , 2008, Current opinion in biotechnology.

[72]  Daniel S Spellman,et al.  Quantitative phosphotyrosine proteomics of EphB2 signaling by stable isotope labeling with amino acids in cell culture (SILAC). , 2006, Journal of proteome research.

[73]  T. Hunter,et al.  Oncogenic kinase signalling , 2001, Nature.

[74]  Tony Pawson,et al.  Interaction domains: from simple binding events to complex cellular behavior , 2002, FEBS letters.

[75]  L. Naldini,et al.  The tyrosine kinase encoded by the MET proto-oncogene is activated by autophosphorylation , 1991, Molecular and cellular biology.

[76]  A. Sorkin,et al.  EGF receptor ubiquitination is not necessary for its internalization , 2007, Proceedings of the National Academy of Sciences.

[77]  J. Schlessinger,et al.  Specific phosphopeptide binding regulates a conformational change in the PI 3‐kinase SH2 domain associated with enzyme activation. , 1993, The EMBO journal.

[78]  Y. Yarden,et al.  Molecular mechanisms underlying endocytosis and sorting of ErbB receptor tyrosine kinases , 2001, FEBS letters.

[79]  G. Carpenter,et al.  Increase of the catalytic activity of phospholipase C-gamma 1 by tyrosine phosphorylation. , 1990, Science.

[80]  Blagoy Blagoev,et al.  Quantitative proteomics to study mitogen-activated protein kinases. , 2006, Methods.

[81]  Jens M. Rick,et al.  Quantitative mass spectrometry in proteomics: a critical review , 2007, Analytical and bioanalytical chemistry.

[82]  B. Blagoev,et al.  Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and Quantitative Comparison of the Membrane Proteomes of Self-renewing and Differentiating Human Embryonic Stem Cells*S , 2009, Molecular & Cellular Proteomics.

[83]  J. Andersen,et al.  Ordered Organelle Degradation during Starvation-induced Autophagy*S , 2008, Molecular & Cellular Proteomics.

[84]  M. Mann,et al.  Proteomic analysis of post-translational modifications , 2003, Nature Biotechnology.

[85]  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.

[86]  M. Mann,et al.  Dissection of the insulin signaling pathway via quantitative phosphoproteomics , 2008, Proceedings of the National Academy of Sciences.

[87]  Gavin MacBeath,et al.  Linear combinations of docking affinities explain quantitative differences in RTK signaling , 2009, Molecular systems biology.

[88]  B. Blagoev,et al.  Signal Transduction by Growth Factor Receptors: Signaling in an Instant , 2007, Cell cycle.

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

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

[91]  M. Karin,et al.  Mitogen-activated protein kinase cascades and regulation of gene expression. , 1996, Current opinion in immunology.

[92]  T. Hunter.  The age of crosstalk: phosphorylation, ubiquitination, and beyond. , 2007, Molecular cell.

[93]  P. Bork,et al.  Systematic Discovery of In Vivo Phosphorylation Networks , 2007, Cell.

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

[95]  M. Mann,et al.  Proteomics to study genes and genomes , 2000, Nature.

[96]  M. Mann,et al.  MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification , 2008, Nature Biotechnology.

[97]  Jonathan A. Cooper,et al.  Protein kinase C phosphorylation of the EGF receptor at a threonine residue close to the cytoplasmic face of the plasma membrane , 1984, Nature.

[98]  R. Aebersold,et al.  Mass spectrometry-based proteomics , 2003, Nature.

[99]  M. Mann,et al.  The abc's (and xyz's) of peptide sequencing , 2004, Nature Reviews Molecular Cell Biology.

[100]  F. Cross,et al.  Accurate quantitation of protein expression and site-specific phosphorylation. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[101]  J. Schlessinger,et al.  Signal transduction by allosteric receptor oligomerization. , 1988, Trends in biochemical sciences.

[102]  M. Mann,et al.  Investigation of Protein-tyrosine Phosphatase 1B Function by Quantitative Proteomics*S , 2008, Molecular & Cellular Proteomics.

[103]  S. Shoelson,et al.  Crystal Structure of the Tyrosine Phosphatase SHP-2 , 1998, Cell.

[104]  T. Pawson,et al.  Protein-protein interactions define specificity in signal transduction. , 2000, Genes & development.

[105]  A. Gordus,et al.  System-wide investigation of ErbB4 reveals 19 sites of Tyr phosphorylation that are unusually selective in their recruitment properties. , 2008, Chemistry & biology.

[106]  Ron Bose,et al.  Phosphoproteomic analysis of Her2/neu signaling and inhibition. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[107]  M. Mann,et al.  Trypsin Cleaves Exclusively C-terminal to Arginine and Lysine Residues*S , 2004, Molecular & Cellular Proteomics.

[108]  S. Hubbard,et al.  Autoregulatory Mechanisms in Protein-tyrosine Kinases* , 1998, The Journal of Biological Chemistry.

[109]  E. Petricoin,et al.  Dynamic Profiling of the Post-translational Modifications and Interaction Partners of Epidermal Growth Factor Receptor Signaling after Stimulation by Epidermal Growth Factor Using Extended Range Proteomic Analysis (ERPA)*S , 2006, Molecular & Cellular Proteomics.

[110]  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.