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Differential Mechanisms for SHP2 Binding and Activation Are Exploited by Geographically Distinct Helicobacter pylori CagA Oncoproteins.

Hayashi T, Senda M, Suzuki N, Nishikawa H, Ben C, Tang C, Nagase L, Inoue K, Senda T, Hatakeyama M
Cell Rep 20 2876-2890 (2017)
Cited: 52 times
EuropePMC logo PMID: 28930683

Abstract

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.

Articles - 5x94 mentioned but not cited (7)

  1. Structural Determinants of Phosphopeptide Binding to the N-Terminal Src Homology 2 Domain of the SHP2 Phosphatase. Anselmi M, Calligari P, Hub JS, Tartaglia M, Bocchinfuso G, Stella L. J Chem Inf Model 60 3157-3171 (2020)
  2. Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state. Calligari P, Santucci V, Stella L, Bocchinfuso G. Comput Struct Biotechnol J 19 6125-6139 (2021)
  3. Exploring the Distinct Binding and Activation Mechanisms for Different CagA Oncoproteins and SHP2 by Molecular Dynamics Simulations. Wang Q, Zhao WC, Fu XQ, Zheng QC. Molecules 26 837 (2021)
  4. Experiment-guided molecular simulations define a heterogeneous structural ensemble for the PTPN11 tandem SH2 domains. Marasco M, Kirkpatrick J, Carlomagno T, Hub JS, Anselmi M. Chem Sci 14 5743-5755 (2023)
  5. Structural Insights into the Binding Propensity of Human SHIP2 SH2 to Oncogenic CagA Isoforms from Helicobacter pylori. Wang Z, Shan Y, Wang R, Zhou H, Hu R, Li Y, Zhu J, Yang Y, Liu M. Int J Mol Sci 23 11299 (2022)
  6. Helicobacter pylori East Asian type CagA hijacks more SHIP2 by its EPIYA-D motif to potentiate the oncogenicity. Ji X, Wu Q, Cao X, Liu S, Zhang J, Chen S, Shan J, Zhang Y, Li B, Zhao H. Virulence 15 2375549 (2024)
  7. research-article The pathogenic T42A mutation in SHP2 rewires the interaction specificity of its N-terminal regulatory domain. van Vlimmeren AE, Voleti R, Chartier CA, Jiang Z, Karandur D, Humphries PA, Lo WL, Shah NH. bioRxiv 2023.07.10.548257 (2024)


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