期刊
CELL REPORTS
卷 22, 期 10, 页码 2784-2796出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.02.038
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资金
- Novo Nordisk Foundation [NNF14CC0001]
- European Union's Horizon research and innovation program [MSmed 686547]
- EMBO fellowship
- Wellcome Trust [8107636/Z/15/Z]
- Danish Cancer Society [R90-A5844 KBVU]
- Lundbeckfonden [R191-2015-703]
Despite its low cellular abundance, phosphotyrosine (pTyr) regulates numerous cell signaling pathways in health and disease. We applied comprehensive phosphoproteomics to unravel differential regulators of receptor tyrosine kinase (RTK)-initiated signaling networks upon activation by Pdgf-bb, Fgf-2, or Igf-1 and identified more than 40,000 phosphorylation sites, including many phosphotyrosine sites without additional enrichment. The analysis revealed RTK-specific regulation of hundreds of pTyr sites on key signaling molecules. We found the tyrosine phosphatase Shp-2 to be the master regulator of Pdgfr pTyr signaling. Application of a recently introduced allosteric Shp-2 inhibitor revealed global regulation of the Pdgf-dependent tyrosine phosphoproteome, which significantly impaired cell migration. In addition, we present a list of hundreds of Shp-2-dependent targets and putative substrates, including Rasa1 and Cortactin with increased pTyr and Gab1 and Erk1/2 with decreased pTyr. Our study demonstrates that large-scale quantitative phosphoproteomics can precisely dissect tightly regulated kinase-phosphatase signaling networks.
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