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RESEARCH PRODUCT

Defining Human Tyrosine Kinase Phosphorylation Networks Using Yeast as an In Vivo Model Substrate.

Federico ApeltJean-fred FontaineArndt GrossmannJohannes HelmuthThomas CorwinBryan A. BallifMiguel A. Andrade-navarroUlrich StelzlUlrich StelzlDavid MeierhoferJonathan WoodsmithJonathan Woodsmith

subject

0301 basic medicineCell signalingHistologySaccharomyces cerevisiae ProteinsSaccharomyces cerevisiaeAmino Acid MotifsSaccharomyces cerevisiaeInteractomeReceptor tyrosine kinaseArticlePathology and Forensic Medicine03 medical and health scienceschemistry.chemical_compoundHumansProtein Interaction MapsPhosphorylationbiologyTyrosine phosphorylationCell BiologyProtein-Tyrosine Kinasesbiology.organism_classificationYeastCell biology030104 developmental biologychemistrybiology.proteinPhosphorylationTyrosine kinaseSequence Alignment

description

Systematic assessment of tyrosine kinase-substrate relationships is fundamental to a better understanding of cellular signaling and its profound alterations in human diseases such as cancer. In human cells, such assessments are confounded by complex signaling networks, feedback loops, conditional activity, and intra-kinase redundancy. Here we address this challenge by exploiting the yeast proteome as an in vivo model substrate. We individually expressed 16 human non-receptor tyrosine kinases (NRTKs) in Saccharomyces cerevisiae and identified 3,279 kinase-substrate relationships involving 1,351 yeast phosphotyrosine (pY) sites. Based on the yeast data without prior information, we generated a set of linear kinase motifs and assigned ∼1,300 known human pY sites to specific NRTKs. Furthermore, experimentally defined pY sites for each individual kinase were shown to cluster within the yeast interactome network irrespective of linear motif information. We therefore applied a network inference approach to predict kinase-substrate relationships for more than 3,500 human proteins, providing a resource to advance our understanding of kinase biology.

10.1016/j.cels.2017.08.001https://pubmed.ncbi.nlm.nih.gov/28837810