title: Phospho-tyrosine dependent protein-protein interaction network.
abstract: 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 (p55γ), we exemplarily provide evidence that the two pY-dependent PPIs dictate cellular cancer phenotypes.
authors: Otto-Warburg Laboratory, Max-Planck Institute for Molecular Genetics (MPIMG), Berlin, Germany.
authors: Arndt
authors: A
authors: Grossmann
authors: Otto-Warburg Laboratory, Max-Planck Institute for Molecular Genetics (MPIMG), Berlin, Germany.
authors: Nouhad
authors: N
authors: Benlasfer
authors: Otto-Warburg Laboratory, Max-Planck Institute for Molecular Genetics (MPIMG), Berlin, Germany.
authors: Petra
authors: P
authors: Birth
authors: Otto-Warburg Laboratory, Max-Planck Institute for Molecular Genetics (MPIMG), Berlin, Germany.
authors: Anna
authors: A
authors: Hegele
authors: Otto-Warburg Laboratory, Max-Planck Institute for Molecular Genetics (MPIMG), Berlin, Germany.
authors: Franziska
authors: F
authors: Wachsmuth
authors: Otto-Warburg Laboratory, Max-Planck Institute for Molecular Genetics (MPIMG), Berlin, Germany.
authors: Luise
authors: L
authors: Apelt
authors: Otto-Warburg Laboratory, Max-Planck Institute for Molecular Genetics (MPIMG), Berlin, Germany stelzl@molgen.mpg.de.
authors: Ulrich
authors: U
authors: Stelzl
mesh_terms: D006801:Humans; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D060066:Protein Interaction Maps; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D020798:Two-Hybrid System Techniques; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D010750:Phosphoproteins; D014443:Tyrosine; D011494:Protein Kinases
keywords: cancer signaling; network biology; post‐translational protein modification; yeast two‐hybrid