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

Hayashi, Tetsuhito; Senda, Masuo; Suzuki, Nobuhiro; Nishikawa, Hiroko; Ben, Chi; Tang, Chao; Nagase, Lisa; Inoué, Kaori; Senda, Toshiya; Hatakeyama, Masanori

doi:10.1016/j.celrep.2017.08.080

Cited by 83 publications

(107 citation statements)

References 30 publications

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“…A quantitative biochemical study revealed that the East Asian CagA (ABD)specific EPIpYA-D peptide binds to the N-SH2 domain of SHP2 100-fold more strongly than the Western CagA (ABC)-specific EPIpYA-C peptide. The phenylalanine (F) residue at the pY + 5 position of the EPIpYA-D peptide was found to form a high-affinity monovalent bond with the hollow pocket on the N-SH2 phosphopeptide-binding floor of SHP2 136 (Fig. 3).…”

Section: Sequence Polymorphisms Of Caga That Confer Differential Oncomentioning

confidence: 99%

Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

2019

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Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor for gastric cancer. The cagA gene product, CagA, is delivered into gastric epithelial cells via the bacterial type IV secretion system. Delivered CagA then undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs in its C-terminal region and acts as an oncogenic scaffold protein that physically interacts with multiple host signaling proteins in both tyrosine phosphorylation-dependent and-independent manners. Analysis of CagA using in vitro cultured gastric epithelial cells has indicated that the nonphysiological scaffolding actions of CagA cell-autonomously promote the malignant transformation of the cells by endowing the cells with multiple phenotypic cancer hallmarks: sustained proliferation, evasion of growth suppressors, invasiveness, resistance to cell death, and genomic instability. Transgenic expression of CagA in mice leads to in vivo oncogenic action of CagA without any overt inflammation. The in vivo oncogenic activity of CagA is further potentiated in the presence of chronic inflammation. Since Helicobacter pylori infection triggers a proinflammatory response in host cells, a feedforward stimulation loop that augments the oncogenic actions of CagA and inflammation is created in CagA-injected gastric mucosa. Given that Helicobacter pylori is no longer colonized in established gastric cancer lesions, the multistep nature of gastric cancer development should include a "hit-and-run" process of CagA action. Thus, acquisition of genetic and epigenetic alterations that compensate for CagA-directed cancer hallmarks may be required for completion of the "hit-and-run" process of gastric carcinogenesis.

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Section: Sequence Polymorphisms Of Caga That Confer Differential Oncomentioning

confidence: 99%

Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

2019

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“…Mutations of PTPN11 (the gene coding for SHP2) cause more than 30% of cases of juvenile myelomonocytic leukemia (JMML) [Tartaglia 2003;2004 a] and are variably found in other childhood malignancies [Tartaglia 2003[Tartaglia , 2004bGrossmann 2010]. In addition, SHP2 is required for survival of receptor tyrosine kinases (RTK)-driven cancer cells [Chen 2016], plays an important role in resistance to targeted cancer drugs [Ahmed 2019], is a mediator of immune checkpoint pathways [Okazaki 2013] and is involved in the induction of gastric carcinoma by H. pylori [Hayashi 2017]. PTPN11 mutations also cause Noonan syndrome and Noonan syndrome with multiple lentigines, two disorders belonging to a family of rare diseases collectively known as RASopathies [Tartaglia 2001;Tartaglia 2004a;Tartaglia 2010].…”

Section: The Sh2 Domain-containing Protein Tyrosine Phosphatasementioning

confidence: 99%

“…Hydrophobic, anionic and cationic residues are colored in green, red and blue, respectively. pY numbers refer to the human sequence, except for H. pylori CagA, where the sequence refers to the EPIYA-D segment [Hayashi 2017]. Relative dissociation constant (Kd) values, are normalized to that of IRS-1 pY1172 [Sugimoto 1994], i.e.…”

Section: Phosphopeptide Sequence Selectivity Of the N-sh2 Domain Of Shp2mentioning

confidence: 99%

Structural Determinants of Phosphopeptide Binding to the N-Terminal Src Homology 2 Domain of the SHP2 Phosphatase

Anselmi

Calligari

Hub

et al. 2020

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ABSTRACTSH2 domain-containing tyrosine phosphatase 2 (SHP2), encoded by PTPN11, plays a fundamental role in the modulation of several signaling pathways. Germline and somatic mutations in PTPN11 are associated with different rare diseases and hematologic malignancies, and recent studies have individuated SHP2 as a central node in oncogenesis and cancer drug resistance. SHP2 structure includes two Src homology 2 domains (N-SH2 and C-SH2) followed by a catalytic protein tyrosine phosphatase (PTP) domain. Under basal conditions, the N-SH2 domain blocks the active site, inhibiting phosphatase activity. Association of the N-SH2 domain with binding partners containing short amino acid motifs comprising a phosphotyrosine residue (pY) leads to N-SH2/PTP dissociation and SHP2 activation. Considering the relevance of SHP2 in signaling and disease and the central role of the N-SH2 domain in its allosteric regulation mechanism, we performed microsecond-long molecular dynamics simulations of the N-SH2 domain complexed to 12 different peptides, to define the structural and dynamical features determining the binding affinity and specificity of the domain. Phosphopeptide residues at position −2 to +5, with respect to pY, have significant interactions with the SH2 domain. In addition to the strong interaction of the pY residue with its conserved binding pocket, the complex is stabilized hydrophobically by insertion of residues +1, +3 and +5 in an apolar groove of the domain, and interaction of residue −2 with both the pY and a protein surface residue. Additional interactions are provided by hydrogen bonds formed by the backbone of residues −1, +1, +2 and +4. Finally, negatively charged residues at position +2 and +4 are involved in electrostatic interactions with two lysines (Lys89 and Lys91) specific of the SHP2 N-SH2 domain. Interestingly, the MD simulations illustrated a previously undescribed conformational flexibility of the domain, involving the core β-sheet and the loop that closes the pY binding pocket.

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“…5,9,10,11,12 Recent studies suggested SHP2 inhibition as a promising strategy for treating a large class of receptor tyrosine kinase-driven cancers 13 and for combating resistance to targeted anticancer therapies. 14,15,16 In addition, SHP2 plays a role in Helicobacter pylori-induced gastric cancer mediated by activation by the bacterial protein CagA, 17 and SHP2 is responsible for the suppression of T-cell activation by programmed cell death-1 (PD-1), a receptor hijacked by tumor cells for evading the immune response. 18 All these recent discoveries indicate SHP2 as an attractive target in future anti-cancer therapies.…”

Section: Introductionmentioning

confidence: 99%

“…According to this hypothesis, phosphopeptide binding to the SH2 domains simply stabilizes the fraction of active SHP2, only after dissociation of N-SH2 from the PTP domain has already taken place. 7,17,28 Second, according to an "induced fit" model, peptide binding might take place in the inactive state of SHP2, triggering the concomitant opening of the protein. 29 However, since the N-SH2 binding site is closed in the inactive state, phosphopeptide binding to the inactive state would require a conformational transition of the N-SH2 domain with respect to the crystal structure.…”

Section: Introductionmentioning

confidence: 99%

An allosteric interaction controls the activation mechanism of SHP2 tyrosine phosphatase

Anselmi

Hub

2020

Preprint

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SHP2 is a protein tyrosine phosphatase with a key role in multiple signaling pathways, including the RAS-MAPK cascade. Germline mutations in PTPN11, the gene encoding SHP2, occur in 50% of individuals affected by Noonan syndrome, whereas somatic mutations in this gene cause more than 30% of cases of juvenile myelomonocytic leukemia (JMML), and are variably found in other pediatric hematologic malignancies and tumors. Inhibition of the wild-type protein has been recently demonstrated as a novel effective therapeutic strategy for many forms of cancer. Under basal conditions, wild-type SHP2 is inactive because its N-terminal Src homology 2 (N-SH2) domain blocks the active site of the protein tyrosine phosphatase (PTP) domain. Previous work established that binding of a phosphopeptide ligand to the N-SH2 domain causes SHP2 activation by favoring dissociation of the N-SH2 and PTP domains, however the conformational transitions of N-SH2 controlling ligand affinity and PTP dissociation are not well understood. Based on molecular simulations and free-energy calculations, we revealed a 20Å-spanning allosteric network restraining the N-SH2 domain to two distinct states, a SHP2-activating and a stabilizing state. We find that ligand binding is necessary but not sufficient for SHP2 activation, as only ligands selecting for the activating conformation of N-SH2, depending on ligand sequence and binding mode, are predicted to be effective activators. The proposed model of SHP2 activation is further validated by rationalizing modified basal activity and responsiveness to ligand stimulation of N-SH2 variations at residue Tyr 42 . This study provides mechanistic and energetic insight into SHP2 activation and may open novel routes for SHP2 regulation.

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

Cited by 83 publications

References 30 publications

Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

Structural Determinants of Phosphopeptide Binding to the N-Terminal Src Homology 2 Domain of the SHP2 Phosphatase

An allosteric interaction controls the activation mechanism of SHP2 tyrosine phosphatase

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