期刊
CELL REPORTS
卷 20, 期 12, 页码 2876-2890出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.08.080
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资金
- CREST [120200000396]
- MEXT, Japan [16H06373, 16K15273, 16K19121, 15K18495]
- Project for Cancer Research and Therapeutic Evolution (P-CREATE) [160200000291]
- PDIS
- Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from AMED, Japan
- Grants-in-Aid for Scientific Research [16H06373, 16K19121, 15K18495, 16K15273] Funding Source: KAKEN
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.
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