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Cell Syst. 2017 Aug 23;5(2):128-139.e4. doi: 10.1016/j.cels.2017.08.001.

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

Author information

1
Otto-Warburg Laboratory, Max-Planck Institute for Molecular Genetics (MPIMG), 14195 Berlin, Germany.
2
Otto-Warburg Laboratory, Max-Planck Institute for Molecular Genetics (MPIMG), 14195 Berlin, Germany; Institute of Pharmaceutical Sciences, University of Graz and BioTechMed-Graz, 8010 Graz, Austria.
3
Genomics and Computational Biology, Kernel Press UG, 55128 Mainz, Germany; Faculty of Biology, Johannes Gutenberg University Mainz and Institute of Molecular Biology, 55128 Mainz, Germany.
4
Faculty of Biology, Johannes Gutenberg University Mainz and Institute of Molecular Biology, 55128 Mainz, Germany.
5
Department of Biology, University of Vermont, Burlington, VT 05405, USA.
6
Otto-Warburg Laboratory, Max-Planck Institute for Molecular Genetics (MPIMG), 14195 Berlin, Germany; Institute of Pharmaceutical Sciences, University of Graz and BioTechMed-Graz, 8010 Graz, Austria. Electronic address: ulrich.stelzl@uni-graz.at.

Abstract

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.

KEYWORDS:

kinase-substrate specificity; network propagation; protein interaction networks; tyrosine phosphorylation

PMID:
28837810
DOI:
10.1016/j.cels.2017.08.001
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