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Helicobacter pylori CagA Induces Ras-independent Morphogenetic Response through SHP-2 Recruitment and Activation
- Source :
- Journal of Biological Chemistry. 279:17205-17216
- Publication Year :
- 2004
- Publisher :
- Elsevier BV, 2004.
-
Abstract
- The CagA protein of Helicobacter pylori, which is injected from the bacteria into bacteria-attached gastric epithelial cells, is associated with gastric carcinoma. CagA is tyrosine-phosphorylated by Src family kinases, binds the SH2 domain-containing SHP-2 phosphatase in a tyrosine phosphorylation-dependent manner, and deregulates its enzymatic activity. We established AGS human gastric epithelial cells that inducibly express wild-type or a phosphorylation-resistant CagA, in which tyrosine residues constituting the EPIYA motifs were substituted with alanines. Upon induction, wild-type CagA, but not the mutant CagA, elicited strong elongation of cell shape, termed the "hummingbird" phenotype. Time-lapse video microscopic analysis revealed that the CagA-expressing cells exhibited a marked increase in cell motility with successive rounds of elongation-contraction processes. Inhibition of CagA phosphorylation by an Src kinase inhibitor, PP2, or knockdown of SHP-2 expression by small interference RNA (siRNA) abolished the CagA-mediated hummingbird phenotype. The morphogenetic activity of CagA also required Erk MAPK but was independent of Ras or Grb2. In AGS cells, CagA prolonged duration of Erk activation in response to serum stimulation. Conversely, inhibition of SHP-2 expression by siRNA abolished the sustained Erk activation. Thus, SHP-2 acts as a positive regulator of Erk activity in AGS cells. These results indicate that SHP-2 is involved in the Ras-independent modification of Erk signals that is necessary for the morphogenetic activity of CagA. Our work therefore suggests a key role of SHP-2 in the pathological activity of H. pylori virulence factor CagA.
- Subjects :
- MAPK/ERK pathway
DNA, Complementary
SH2 Domain-Containing Protein Tyrosine Phosphatases
Time Factors
Genetic Vectors
Immunoblotting
Phosphatase
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Biology
Transfection
digestive system
Biochemistry
Cell Line
Bacterial Proteins
Animals
Humans
CagA
Phosphorylation
RNA, Small Interfering
Tyrosine
Molecular Biology
Antigens, Bacterial
Microscopy, Video
Helicobacter pylori
Kinase
Stomach
Intracellular Signaling Peptides and Proteins
Cell Biology
bacterial infections and mycoses
Precipitin Tests
Molecular biology
digestive system diseases
Enzyme Activation
Phenotype
COS Cells
ras Proteins
biology.protein
bacteria
RNA Interference
GRB2
Mitogen-Activated Protein Kinases
Protein Tyrosine Phosphatases
Proto-oncogene tyrosine-protein kinase Src
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 279
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....5463e80c6c145d8be0c4fceb11601e57