Phosphotyrosine interactome of the ErbB-receptor kinase family

By Waltraud X. Schulze, Lei Deng, Matthias Mann. Molecular Systems Biology, 2005

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Interactions between short modified peptide motifs and modular protein domains are central events in cell signal‐transduction. We determined interaction partners to all cytosolic tyrosine residues of the four members of the ErbB‐receptor family in an unbiased fashion by quantitative proteomics using pull‐down experiments with pairs of phosphorylated and nonphosphorylated synthetic peptides. Each receptor had characteristic preferences for interacting proteins and most interaction partners had multiple binding sites on each receptor. EGFR and ErbB4 had several docking sites for Grb2, while ErbB3 was characterized by six binding sites for PI3K. We identified STAT5 as a direct binding partner to EGFR and ErbB4 and discovered new recognition motifs for Shc and STAT5. The overall pattern of interaction partners of EGFR and ErbB4 suggests similar roles during signaling through their respective ligands. Phosphorylation kinetics of several tyrosine resides was measured by mass spectrometry and correlated with interaction partner preference. Our results demonstrate that system‐wide mapping of peptide‐protein interactions sites is possible, and suggest shared and unique roles of ErbB‐receptor family members in downstream signaling.

Subfields: Molecular Biology, Oncology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/439b1dc3e9af977737f0dbbddca9a20cd30c6816

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Citations in the corpus

The epidermal growth factor receptor family: Biology driving targeted therapeutics (2008, background): “EGFR and ErbB4 can be thought of as fully functional receptors with the ability to both bind ligands and autophosphorylate C-terminal tails through functional intracellular tyrosine kinase domains.”
ErbB receptors and signaling pathways in cancer. (2009, background): “Large-scale phosphoproteomic screening revealed that ErbB receptors potentially bind >100 proteins [28,29].”
Linear Motif Atlas for Phosphorylation-Dependent Signaling (2008, methodology): “We extended this data set by curating data from in vitro assays ( 28 , 48 , 49 ).”
EGF–ERBB signalling: towards the systems level (2006, background): “Several tyrosine-based motifs recruit a number of signal transducers to the phosphorylated form of ERBB1 (Ref”
The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis (2007, background): “HER2 lacks binding sites for the p85 subunit of PI3K, whereas HER3 has seven p85binding phosphotyrosine-containing motifs (Prigent and Gullick, 1994; Soltoff et al., 1994; Schulze et al., 2005).”
Reading protein modifications with interaction domains (2006, background): “Activated receptor tyrosine kinases (RTKs), such as the β-platelet-derived growth factor receptor or the epidermal growth factor receptor (EGFR), become phosphorylated at multiple Tyr sites, and each of these sites selectively binds the SH2 domain of one or more cytoplasmic signalling proteins, whic”
Input–output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data (2009, background): “10 7 states (Schulze et al , 2005).”
Decoding signalling networks by mass spectrometry-based proteomics (2010, methodology): “In a reverse approach, synthetic peptides containing phosphorylated or non-phosphorylated Tyr were incubated with SILAC-labelled cell lysates to characterize the phosphoTyr-dependent interactome of the ERBB receptor kinase family and of the insulin receptor family and its downstream effectors insuli”