Effects of Halogenation on Tyrosine Phosphorylation and Peptide Binding to the Src Homology 2 Domain of Lymphocyte-Specific Protein Tyrosine Kinase
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概要
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Phosphorylation of tyrosine residues by protein tyrosine kinases (PTK) and phosphotyrosine/Src homology 2 (SH2) domain interactions are crucial not only for signal transduction but also for regulation of PTK activity. Tyrosine residues also receive nitration and halogenation under oxidative conditions. It has been reported that nitration of tyrosine residue caused peptides to be a poor substrate for PTK and that nitrotyrosine residues could bind to SH2 domains as a phosphotyrosine mimic to activate Src family kinase. However, the effect of halogenation on tyrosine phosphorylation or SH2 domain binding is not well understood. We examined the phosphorylation of model peptides containing 3-halotyrosine or 3-nitrotyrosine using typical receptor tyrosine kinase, epidermal growth factor receptor (EGFR), and nonreceptor tyrosine kinase, lymphocyte-specific protein tyrosine kinase (Lck). The EGFR- and Lck-mediated phosphorylation was markedly inhibited by tyrosine halogenation. Iodination showed the strongest inhibition of the phosphorylation among four types of halogenation, and its inhibitory effect was stronger than that of nitration. We also examined the effect of iodination and nitration of tyrosine residues on binding to the SH2 domain of Lck, using a model peptide containing the phosphoTyr-Glu-Glu-Ile motif, which has a high affinity for the SH2 domain. The relative affinities of the modified peptides whose phosphotyrosine was substituted with unphosphorylated tyrosine, 3-nitrotyrosine, and 3-iodotyrosine, and of the model peptide were 0.024, 0.26, 1, and 16, respectively. These results suggest that tyrosine iodination may have an effect on the phosphorylation or binding to the SH2 domain similar to nitration. Tyrosine iodination possibly modulates signal transduction, with the potential impairment of cell function.
著者
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Odaka Kenichi
Molecular Imaging Center National Institute Of Radiological Sciences
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Irie Toshiaki
Molecular Imaging Center National Institute Of Radiological Sciences
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Fukushi Kiyoshi
Molecular Probe Group Molecular Imaging Center National Inst. Of Radiological Sciences
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Kikuchi Tatsuya
Molecular Probe Group, Molecular Imaging Center, National Institute of Radiological Sciences
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Okamura Toshimitsu
Molecular Probe Group, Molecular Imaging Center, National Institute of Radiological Sciences
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Odaka Kenichi
Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences
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Nodaira Mika
Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences
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Okamura Toshimitsu
Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences
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Kikuchi Tatsuya
Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences
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Irie Toshiaki
Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences
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Fukushi Kiyoshi
Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences
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