期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 140, 期 41, 页码 13253-13259出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.8b06922
关键词
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资金
- National Key Research and Development Program of China [2016YFA0201400]
- National Natural Science Foundation of China [21778005]
- Peking University Health Science Center [BMU20160537, BMU2017QQ006]
- Youth Thousand-Talents Program of China
Protein tyrosine phosphatases (PTPs) play critical roles in cell signaling pathways, but identification of unknown PTPs for a given substrate in live cells remain technically challenging. Here, we synthesized a series of tyrosine-based irreversible PTP inhibitors and characterized by site-specific encoding on substrate proteins in cells with an expanded genetic code. By fine-tuning the chemical reactivity, we identified optimal active amino acid probes to covalently cross-link a PTP and its substrate both in vitro and in mammalian cells. Using HER2 as an example, we provide first direct evidence of HER2 Y1023 and SHP2 cross-linking in situ in living human cells. Moreover, proteomic analysis using our approach identified PTP1B as a novel phosphatase for HER2 that specifically dephosphorylated pY1221 position, which may shed light on the puzzle of PTP1B's role in HER2 positive breast cancer. This novel method provides a useful tool for dissecting tyrosine phosphoregulation in living cells.
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