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著者: Takeru Hayashi, Miki Senda, Nobuhiro Suzuki, Hiroko Nishikawa, Chi Ben, Chao Tang, Lisa Nagase, Kaori Inoue, Toshiya Senda, Masanori Hatakeyama
雑誌名: Cell Rep. 2017 Sep 19;20(12):2876-2890. doi: 10.1016/j.celrep.2017.08.080.
Abstract/Text
Helicobacter pylori East Asian CagA is more closely associated with gastric cancer than Western CagA. Here we show that, upon tyrosine phosphorylation, the East Asian CagA-specific EPIYA-D segment binds to the N-SH2 domain of pro-oncogenic SHP2 phosphatase two orders of magnitude greater than Western CagA-specific EPIYA-C. This high-affinity binding is achieved via cryptic interaction between Phe at the +5 position from phosphotyrosine in EPIYA-D and a hollow on the N-SH2 phosphopeptide-binding floor. Also, duplication of EPIYA-C in Western CagA, which increases gastric cancer risk, enables divalent high-affinity binding with SHP2 via N-SH2 and C-SH2. These strong CagA bindings enforce enzymatic activation of SHP2, which endows cells with neoplastic traits. Mechanistically, N-SH2 in SHP2 is in an equilibrium between stimulatory "relaxed" and inhibitory "squeezed" states, which is fixed upon high-affinity CagA binding to the "relaxed" state that stimulates SHP2. Accordingly, East Asian CagA and Western CagA exploit distinct mechanisms for SHP2 deregulation.
Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
PMID 28930683 Cell Rep. 2017 Sep 19;20(12):2876-2890. doi: 10.1016/j.celrep.2017.08.080.
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