The SH2 domain interaction landscape.

Members of the SH2 domain family modulate signal transduction by binding to short peptides containing phosphorylated tyrosines. Each domain displays a distinct preference for the sequence context of the phosphorylated residue. We have developed a high-density peptide chip technology that allows for probing of the affinity of most SH2 domains for a large fraction of the entire complement of tyrosine phosphopeptides in the human proteome. Using this technique, we have experimentally identified thousands of putative SH2-peptide interactions for more than 70 different SH2 domains. By integrating this rich data set with orthogonal context-specific information, we have assembled an SH2-mediated probabilistic interaction network, which we make available as a community resource in the PepspotDB database. A predicted dynamic interaction between the SH2 domains of the tyrosine phosphatase SHP2 and the phosphorylated tyrosine in the extracellular signal-regulated kinase activation loop was validated by experiments in living cells.

[1]  Andrew Chatr-aryamontri,et al.  DOMINO: a database of domain–peptide interactions , 2006, Nucleic Acids Res..

[2]  C. Sander,et al.  The HUPO PSI's Molecular Interaction format—a community standard for the representation of protein interaction data , 2004, Nature Biotechnology.

[3]  Zsuzsanna Dosztányi,et al.  IUPred: web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content , 2005, Bioinform..

[4]  T. Pawson,et al.  The human and mouse complement of SH2 domain proteins-establishing the boundaries of phosphotyrosine signaling. , 2006, Molecular cell.

[5]  C. Eyers.  Universal sample preparation method for proteome analysis , 2009 .

[6]  M. Mann,et al.  Universal sample preparation method for proteome analysis , 2009, Nature Methods.

[7]  Tony Pawson,et al.  Specificity in Signal Transduction From Phosphotyrosine-SH2 Domain Interactions to Complex Cellular Systems , 2004, Cell.

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

[9]  P. Bork,et al.  Linear Motif Atlas for Phosphorylation-Dependent Signaling , 2008, Science Signaling.

[10]  Adam Godzik,et al.  Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences , 2006, Bioinform..

[11]  N. Blom,et al.  Sequence and structure-based prediction of eukaryotic protein phosphorylation sites. , 1999, Journal of molecular biology.

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

[13]  The UniProt Consortium,et al.  The Universal Protein Resource (UniProt) 2009 , 2008, Nucleic Acids Res..

[14]  M. Moran,et al.  Binding of SH2 domains of phospholipase C gamma 1, GAP, and Src to activated growth factor receptors. , 1990, Science.

[15]  L. Castagnoli,et al.  Methods to reveal domain networks. , 2005, Drug discovery today.

[16]  Gary D Bader,et al.  Rapid Evolution of Functional Complexity in a Domain Family , 2009, Science Signaling.

[17]  Tony Pawson,et al.  Defining the Specificity Space of the Human Src Homology 2 Domain*S , 2008, Molecular & Cellular Proteomics.

[18]  Gautier Koscielny,et al.  Ensembl 2012 , 2011, Nucleic Acids Res..

[19]  Allegra Via,et al.  Phospho.ELM: a database of phosphorylation sites—update 2008 , 2007, Nucleic Acids Res..

[20]  O. Lund,et al.  novel sequence representations Reliable prediction of T-cell epitopes using neural networks with , 2003 .

[21]  R. Frank.  Spot-synthesis: an easy technique for the positionally addressable, parallel chemical synthesis on a membrane support , 1992 .

[22]  A. Godwin,et al.  A Grb2-associated docking protein in EGF- and insulin-receptor signalling , 1996, Nature.

[23]  Gianni Cesareni,et al.  In Vitro Evolution of Recognition Specificity Mediated by SH3 Domains Reveals Target Recognition Rules* , 2002, The Journal of Biological Chemistry.

[24]  G. Cesareni,et al.  Comparative interactomics: comparing apples and pears? , 2007, Trends in biotechnology.

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

[26]  T. Pawson,et al.  SH2 domains recognize specific phosphopeptide sequences , 1993, Cell.

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

[28]  Allegra Via,et al.  Phospho.ELM: a database of phosphorylation sites—update 2008 , 2008, Nucleic Acids Res..

[29]  M. Mann,et al.  The Phosphotyrosine Interactome of the Insulin Receptor Family and Its Substrates IRS-1 and IRS-2*S , 2009, Molecular & Cellular Proteomics.

[30]  Robert Hoffmann,et al.  HomoMINT: an inferred human network based on orthology mapping of protein interactions discovered in model organisms , 2005, BMC Bioinformatics.

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

[32]  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.

[33]  Livia Perfetto,et al.  MINT, the molecular interaction database: 2012 update , 2011, Nucleic Acids Res..

[34]  Vladimir Vacic,et al.  Two Sample Logo: a graphical representation of the differences between two sets of sequence alignments , 2006, Bioinform..

[35]  J. Kornhauser,et al.  PhosphoSite: A bioinformatics resource dedicated to physiological protein phosphorylation , 2004, Proteomics.

[36]  Maria Victoria Schneider,et al.  MINT: a Molecular INTeraction database. , 2002, FEBS letters.

[37]  Gary D Bader,et al.  The multiple-specificity landscape of modular peptide recognition domains. , 2011 .

[38]  Qi Zhu,et al.  PepCyber:P∼PEP: a database of human protein–protein interactions mediated by phosphoprotein-binding domains , 2007, Nucleic Acids Res..

[39]  Tony Pawson,et al.  High-throughput phosphotyrosine profiling using SH2 domains. , 2007, Molecules and Cells.

[40]  T Pawson,et al.  Src homology region 2 domains direct protein-protein interactions in signal transduction. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[41]  J. Schneider-Mergener,et al.  Coherent membrane supports for parallel microsynthesis and screening of bioactive peptides. , 2000, Biopolymers.

[42]  Brett W. Engelmann,et al.  SH2 Domains Recognize Contextual Peptide Sequence Information to Determine Selectivity* , 2010, Molecular & Cellular Proteomics.

[43]  G. Ragsdell.  Systems , 2002, Economics of Visual Art.

[44]  Bin Zhang,et al.  PhosphoSitePlus: a comprehensive resource for investigating the structure and function of experimentally determined post-translational modifications in man and mouse , 2011, Nucleic Acids Res..

[45]  Luana Licata,et al.  Protein interactions: integration leads to belief. , 2008, Trends in biochemical sciences.

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

[47]  Tony Pawson,et al.  SH2 domain specificity and activity modified by a single residue , 1994, Nature.

[48]  Jaap Heringa,et al.  Multi-Harmony: detecting functional specificity from sequence alignment , 2010, Nucleic Acids Res..

[49]  S. Batalov,et al.  A gene atlas of the mouse and human protein-encoding transcriptomes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Cathy H. Wu,et al.  The Universal Protein Resource (UniProt) , 2004, Nucleic Acids Res..