Phospho‐tyrosine dependent protein–protein interaction network

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Zeitschriftentitel:	Molecular Systems Biology
Personen und Körperschaften:	Grossmann, Arndt, Benlasfer, Nouhad, Birth, Petra, Hegele, Anna, Wachsmuth, Franziska, Apelt, Luise, Stelzl, Ulrich
In:	Molecular Systems Biology, 11, 2015, 3
Format:	E-Article
Sprache:	Englisch
veröffentlicht:	Springer Science and Business Media LLC
Schlagwörter:	Applied Mathematics Computational Theory and Mathematics General Agricultural and Biological Sciences General Immunology and Microbiology General Biochemistry, Genetics and Molecular Biology Information Systems

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Zusammenfassung:	<jats:title>Abstract</jats:title><jats:p>Post‐translational protein modifications, such as tyrosine phosphorylation, regulate protein–protein interactions (<jats:styled-content style="fixed-case">PPI</jats:styled-content>s) 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 (<jats:styled-content style="fixed-case">pY</jats:styled-content>)‐dependent <jats:styled-content style="fixed-case">PPI</jats:styled-content>s in a direct experimental, large‐scale approach. We identified 292 mostly novel <jats:styled-content style="fixed-case">pY</jats:styled-content>‐dependent <jats:styled-content style="fixed-case">PPI</jats:styled-content>s 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 <jats:styled-content style="fixed-case">pY</jats:styled-content>‐<jats:styled-content style="fixed-case">PPI</jats:styled-content>s are mediated by other linear epitopes or governed by alternative recognition modes. Network analysis revealed that <jats:styled-content style="fixed-case">pY</jats:styled-content>‐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 <jats:styled-content style="fixed-case">pY</jats:styled-content>‐dependent interactions of <jats:styled-content style="fixed-case">TSPAN</jats:styled-content>2 (tetraspanin 2) and <jats:styled-content style="fixed-case">GRB</jats:styled-content>2 or <jats:styled-content style="fixed-case">PIK</jats:styled-content>3R3 (p55γ), we exemplarily provide evidence that the two <jats:styled-content style="fixed-case">pY</jats:styled-content>‐dependent <jats:styled-content style="fixed-case">PPI</jats:styled-content>s dictate cellular cancer phenotypes.</jats:p>
ISSN:	1744-4292
DOI:	10.15252/msb.20145968