SHP-2 Tyrosine Phosphatase as an Intracellular Target of
            <i>Helicobacter pylori</i>
            CagA Protein

Higashi, Hideaki; Tsutsumi, Ryouhei; Muto, Syuichi; Sugiyama, Toshiro; Azuma, Takeshi; Asaka, Masahiro; Hatakeyama, Masanori

doi:10.1126/science.1067147

Cited by 944 publications

(977 citation statements)

References 25 publications

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“…Development of gastric carcinoma is closely associated with cagA-positive Helicobacter pylori infection. H. pylori CagA is delivered into gastric epithelial cells, where it binds to and deregulates SHP-2 (Higashi et al, 2002;Hatakeyama, 2004). The CagA-associated/ deregulated SHP-2 might behave like T507K SHP-2 to promote gastric carcinogenesis.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…pSP65SRa-WT-CagA and pSP65SRa-PR-CagA were described previously (Higashi et al, 2002). TOPtkLuciferase and FOPtkLuciferase plasmids were described previously (Tago et al, 2000).…”

Section: Expression Vectorsmentioning

confidence: 99%

“…The cagA gene product CagA is delivered into H. pylori-attached gastric epithelial cells via the type IV secretion system (Segal et al, 1999;Odenbreit et al, 2000). Upon tyrosine phosphorylation by Src family kinases, CagA binds and activates SHP-2 tyrosine phosphatase to induce an elongated cell shape termed the 'hummingbird phenotype' (Higashi et al, 2002(Higashi et al, , 2004. CagA also interacts with and deregulates a number of cellular proteins such as Grb2, c-Met and ZO-1 in a phosphorylation-independent manner (Mimuro et al, 2002;Amieva et al, 2003;Churin et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells

et al. 2007

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Infection with Helicobacter pylori cagA-positive strains is associated with gastric adenocarcinoma. Intestinal metaplasia is a precancerous lesion of the stomach characterized by transdifferentiation of the gastric mucosa to an intestinal phenotype. The H. pylori cagA gene product, CagA, is delivered into gastric epithelial cells, where it undergoes tyrosine phosphorylation by Src family kinases. Tyrosine-phosphorylated CagA specifically binds to and activates SHP-2 phosphatase, thereby inducing cell-morphological transformation. We report here that CagA physically interacts with E-cadherin independently of CagA tyrosine phosphorylation. The CagA/E-cadherin interaction impairs the complex formation between E-cadherin and b-catenin, causing cytoplasmic and nuclear accumulation of b-catenin. CagA-deregulated b-catenin then transactivates b-catenin-dependent genes such as cdx1, which encodes intestinal specific CDX1 transcription factor. In addition to b-catenin signal, CagA also transactivates p21 WAF1/Cip1 , again, in a phosphorylation-independent manner. Consequently, CagA induces aberrant expression of an intestinal-differentiation marker, goblet-cell mucin MUC2, in gastric epithelial cells that have been arrested in G1 by p21 WAF1/Cip1 . These results indicate that perturbation of the E-cadherin/b-catenin complex by H. pylori CagA plays an important role in the development of intestinal metaplasia, a premalignant transdifferentiation of gastric epithelial cells from which intestinal-type gastric adenocarcinoma arises.

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“…Additionally, CagA interacts with Src homology-2 (SH2) domain-containing proteins. A CagA interaction with the tyrosine phosphatase SHP2 stimulates SHP2 phosphatase activity, which, in turn, might be responsible for the observed dephosphorylation of several cellular proteins 92 . Intriguingly, CagA also interacts with the hepatocyte growth factor/scatter factor (HGF/SF) receptor, c-MET, which is involved in invasive growth of tumour cells.…”

Section: H Pylori Caga Transfermentioning

confidence: 99%

The versatile bacterial type IV secretion systems

Cascales¹,

Christie²

2003

Nat Rev Microbiol

589

559

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Bacteria use type IV secretion systems for two fundamental objectives related to pathogenesisgenetic exchange and the delivery of effector molecules to eukaryotic target cells. Whereas gene acquisition is an important adaptive mechanism that enables pathogens to cope with a changing environment during invasion of the host, interactions between effector and host molecules can suppress defence mechanisms, facilitate intracellular growth and even induce the synthesis of nutrients that are beneficial to bacterial colonization. Rapid progress has been made towards defining the structures and functions of type IV secretion machines, identifying the effector molecules, and elucidating the mechanisms by which the translocated effectors subvert eukaryotic cellular processes during infection. The year 2003 marks the fiftieth anniversary of the first description of a TYPE IV SECRETION (T4S)SYSTEM: the CONJUGATION apparatus of the F plasmid 1 . This is a dynamic bacterial surface organelle, the activities of which are now known to include the contact-dependent delivery of DNA to bacterial recipients and the assembly and retraction of a conjugal PILUS 2 . In the past decade, reports describing systems that are ancestrally related to the F-transfer system and other conjugation machines have emerged. Instead of mediating DNA transfer between bacteria, these systems deliver DNA or protein substrates, known as effectors, to eukaryotic target cells during infection [3][4][5] . More recently, several new T4S systems have been described that are also ancestrally related to the conjugation machines, but these systems mediate the exchange of DNA with the extracellular milieu [6][7][8] . Collectively, this diversity of function in the face of a common ancestry makes the T4S machines attractive subjects for comparative studies that explore the dynamics of organelle assembly and action. Additionally, from a medical perspective, it is of enormous interest to develop a detailed understanding of how the inter-kingdom transfer of type IV effector molecules contributes to pathogenesis. This review will summarize the recent advances in our knowledge of T4S, NIH Public Access Author ManuscriptNat Rev Microbiol. Author manuscript; available in PMC 2013 December 27. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscriptwith an emphasis on machine structure and function, and the activities of effectors after translocation into the eukaryotic host. The T4S familyThis fascinatingly versatile translocation family can be classified into three subfamilies, each of which contributes in unique ways to pathogenesis ( Fig. 1; Table 1). The largest subfamily, the conjugation systems, are found in most species of Gram-negative and Grampositive bacteria. These systems mediate DNA transfer both within and between phylogenetically diverse species, and some systems even deliver DNA to fungi, plants and human cells 2,9-13 . Conjugation is an important contributor to genome plasticity, and therefore bacterial fitness under changing en...

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SHP-2 Tyrosine Phosphatase as an Intracellular Target of Helicobacter pylori CagA Protein

Cited by 944 publications

References 25 publications

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

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

Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells

The versatile bacterial type IV secretion systems

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