Open AccessPhosphotyrosine interactome of the ErbB‐receptor kinase family
Author(s) -
Schulze Waltraud X,
Deng Lei,
Mann Matthias
Publication year - 2005
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.1038/msb4100012
Subject(s) - biology , erbb , grb2 , phosphotyrosine binding domain , erbb3 , erbb4 , receptor tyrosine kinase , signal transduction , phosphorylation , phosphopeptide , interactome , sh2 domain , microbiology and biotechnology , biochemistry , computational biology , gene
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.