| Autor: |
Hayashi, Takeru, Senda, Miki, Suzuki, Nobuhiro, Nishikawa, Hiroko, Ben, Chi, Tang, Chao, Nagase, Lisa, Inoue, Kaori, Senda, Toshiya, Hatakeyama, Masanori |
| Zdroj: |
Cell Reports; September 2017, Vol. 20 Issue: 12 p2876-2890, 15p |
| Abstrakt: |
Helicobacter pyloriEast 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. |
| Databáze: |
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