期刊
MOLECULAR SYSTEMS BIOLOGY
卷 11, 期 3, 页码 -出版社
WILEY
DOI: 10.15252/msb.20145968
关键词
cancer signaling; network biology; post-translational protein modification; yeast two-hybrid
资金
- Max Planck Society
- German Ministry of Science (NGFNp) [NeuroNet-TP3 01GS08171]
- German Ministry of Science (BMBF) [0315082]
Post-translational protein modifications, such as tyrosine phosphorylation, regulate protein-protein interactions (PPIs) critical for signal processing and cellular phenotypes. We extended an established yeast two-hybrid system employing human protein kinases for the analyses of phospho-tyrosine (pY)-dependent PPIs in a direct experimental, large-scale approach. We identified 292 mostly novel pY-dependent PPIs which showed high specificity with respect to kinases and interacting proteins and validated a large fraction in co-immunoprecipitation experiments from mammalian cells. About one-sixth of the interactions are mediated by known linear sequence binding motifs while the majority of pY-PPIs are mediated by other linear epitopes or governed by alternative recognition modes. Network analysis revealed that pY-mediated recognition events are tied to a highly connected protein module dedicated to signaling and cell growth pathways related to cancer. Using binding assays, protein complementation and phenotypic readouts to characterize the pY-dependent interactions of TSPAN2 (tetraspanin 2) and GRB2 or PIK3R3 (p55), we exemplarily provide evidence that the two pY-dependent PPIs dictate cellular cancer phenotypes.
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