Phosphotyrosine interactome of the ErbB-receptor kinase family

被引:387
作者
Schulze, Waltraud X. [1 ]
Deng, Lei [1 ]
Mann, Matthias [1 ]
机构
[1] Univ So Denmark, Dept Biochem & Mol Biol, Ctr Expt Bioinformat, DK-5230 Odense, Denmark
关键词
phosphorylation; post-translational modification; protein-protein interaction; receptor tyrosine kinase signaling; SILAC;
D O I
10.1038/msb4100012
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
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页数:13
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