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Global phosphoproteomic effects of natural tyrosine kinase inhibitor, genistein, on signaling pathways
Author(s) -
Yan GuangRong,
Xiao ChuanLe,
He GuiWei,
Yin XingFeng,
Chen NanPeng,
Cao Ya,
He QingYu
Publication year - 2010
Publication title -
proteomics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.26
H-Index - 167
eISSN - 1615-9861
pISSN - 1615-9853
DOI - 10.1002/pmic.200900662
Subject(s) - genistein , signal transduction , tyrosine kinase inhibitor , tyrosine kinase , phosphorylation , microbiology and biotechnology , biology , kinase , tyrosine , chemistry , biochemistry , cancer , genetics
Abstract Genistein is a natural protein tyrosine kinase inhibitor that exerts anti‐cancer effect by inducing G2/M arrest and apoptosis. However, the phosphotyrosine signaling pathways mediated by genistein are largely unknown. In this study, we combined tyrosine phosphoprotein enrichment with MS‐based quantitative proteomics technology to globally identify genistein‐regulated tyrosine phosphoproteins aiming to depict genistein‐inhibited phosphotyrosine cascades. Our experiments resulted in the identification of 213 phosphotyrosine sites on 181 genistein‐regulated proteins. Many identified phosphoproteins, including nine protein kinases, eight receptors, five protein phosphatases, seven transcriptical regulators and four signal adaptors, were novel inhibitory effectors with no previously known function in the anti‐cancer mechanism of genistein. Functional analysis suggested that genistein‐regulated protein tyrosine phosphorylation mainly by inhibiting the activity of tyrosine kinase EGFR, PDGFR, insulin receptor, Abl, Fgr, Itk, Fyn and Src. Core signaling molecules inhibited by genistein can be functionally categorized into the canonial Receptor‐MAPK or Receptor‐PI3K/AKT cascades. The method used here may be suitable for the identification of inhibitory effectors and tyrosine kinases regulated by anti‐cancer drugs.