Focal Adhesion Kinase Is a Substrate and Downstream Effector of SHP-2 Complexed with <i>Helicobacter pylori</i> CagA

Tsutsumi, Ryouhei; Takahashi, Atsushi; Azuma, Takeshi; Higashi, Hideaki; Hatakeyama, Masanori

doi:10.1128/mcb.26.1.261-276.2006

Cited by 203 publications

(149 citation statements)

References 62 publications

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“…Obviously, however, the notion does not exclude the possibility that host responses to H. pylori infection, such as production of a variety of inflammatory cytokines, potentiate the weak oncogenic activity of CagA. It is also possible that low levels of CagA elicits gastric epithelial cell proliferation, whereas high levels of CagA triggers apoptosis, possibly by inducing oncogenic stress as described (14)(15)(16).…”

Section: Discussionmentioning

confidence: 91%

“…Tyrosine-phosphorylated CagA then specifically binds to and aberrantly activates SHP-2 tyrosine phosphatase (9,14), a bona fide oncoprotein whose gain-of-function mutations are associated with human malignancies (13). CagA-deregulated SHP-2 perturbs the Erk MAP kinase (15) and also dephosphorylates focal adhesion kinase (FAK) to induce an elongated cell-shape known as the hummingbird phenotype (8,16). In addition, CagA interacts with Grb2 and c-Met in a phosphorylation-independent manner (17,18) and Crk in a phosphorylation-dependent manner (19), which may have additional roles in the morphogenetic activity of CagA.…”

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confidence: 99%

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Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse

Ohnishi

Yuasa

Tanaka

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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542

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Infection with cagA-positive Helicobacter pylori is associated with gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma of B cell origin. The cagA-encoded CagA protein is delivered into gastric epithelial cells via the bacterial type IV secretion system and, upon tyrosine phosphorylation by Src family kinases, specifically binds to and aberrantly activates SHP-2 tyrosine phosphatase, a bona fide oncoprotein in human malignancies. CagA also elicits junctional and polarity defects in epithelial cells by interacting with and inhibiting partitioning-defective 1 (PAR1)/microtubule affinity-regulating kinase (MARK) independently of CagA tyrosine phosphorylation. Despite these CagA activities that contribute to neoplastic transformation, a causal link between CagA and in vivo oncogenesis remains unknown. Here, we generated transgenic mice expressing wild-type or phosphorylation-resistant CagA throughout the body or predominantly in the stomach. Wild-type CagA transgenic mice showed gastric epithelial hyperplasia and some of the mice developed gastric polyps and adenocarcinomas of the stomach and small intestine. Systemic expression of wild-type CagA further induced leukocytosis with IL-3/GM-CSF hypersensitivity and some mice developed myeloid leukemias and B cell lymphomas, the hematological malignancies also caused by gain-of-function SHP-2 mutations. Such pathological abnormalities were not observed in transgenic mice expressing phosphorylation-resistant CagA. These results provide first direct evidence for the role of CagA as a bacterium-derived oncoprotein (bacterial oncoprotein) that acts in mammals and further indicate the importance of CagA tyrosine phosphorylation, which enables CagA to deregulate SHP-2, in the development of H. pyloriassociated neoplasms.bacterial oncoprotein ͉ transgenic mouse

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Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse

Ohnishi

Yuasa

Tanaka

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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542

450

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“…A remarkable and key property of CagA is that it can modify several types of cell-to cell junctions (22). In particular, CagA colocalizes with and affects FAK and vinculin phosphorylation at FAs (7,23,24). CagA also disrupts the E-cadherin/β-catenin complex at adherens junctions (8,9).…”

Section: Resultsmentioning

confidence: 99%

Structural insights into Helicobacter pylori oncoprotein CagA interaction with β1 integrin

Türköz

Jiménez‐Soto

Dian

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

116

135

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Infection with the gastric pathogen Helicobacter pylori is a risk factor for the development of gastric cancer. Pathogenic strains of H. pylori carry a type IV secretion system (T4SS) responsible for the injection of the oncoprotein CagA into host cells. H. pylori and its cag -T4SS exploit α5β1 integrin as a receptor for CagA translocation. Injected CagA localizes to the inner leaflet of the host cell membrane, where it hijacks host cell signaling and induces cytoskeleton reorganization. Here we describe the crystal structure of the N-terminal ∼100-kDa subdomain of CagA at 3.6 Å that unveils a unique combination of folds. The core domain of the protein consists of an extended single-layer β-sheet stabilized by two independent helical subdomains. The core is followed by a long helix that forms a four-helix helical bundle with the C-terminal domain. Mapping of conserved regions in a set of CagA sequences identified four conserved surface-exposed patches (CSP1–4), which represent putative hot-spots for protein–protein interactions. The proximal part of the single-layer β-sheet, covering CSP4, is involved in specific binding of CagA to the β1 integrin, as determined by yeast two-hybrid and in vivo competition assays in H. pylori cell-culture infection studies. These data provide a structural basis for the first step of CagA internalization into host cells and suggest that CagA uses a previously undescribed mechanism to bind β1 integrin to mediate its own translocation.

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“…Mammalian expression vectors for SHP-2 and HRAS V12 were described previously (Higashi et al, 2004;Tsutsumi et al, 2006). cDNAs encoding mutant SHP-2 proteins were made from PTPN11 cDNA by site-directed mutagenesis and were cloned into pSP65SRa vector.…”

Section: Plasmidsmentioning

confidence: 99%

“…Immunoprecipitation and immunoblotting SHP-2 substrate-trapping assay was performed as described previously (Tsutsumi et al, 2006). In brief, AGS cells were transfected with wild type or mutant SHP-2-expressing vector and were cultured in PRMI1640 medium containing 10% FBS.…”

Section: Molecular Modelingmentioning

confidence: 99%

Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors

Miyamoto

Takahashi

et al. 2008

Oncogene

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Focal Adhesion Kinase Is a Substrate and Downstream Effector of SHP-2 Complexed with Helicobacter pylori CagA

Cited by 203 publications

References 62 publications

Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse

Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse

Structural insights into Helicobacter pylori oncoprotein CagA interaction with β1 integrin

Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors

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