The CagA Protein ofHelicobacter pyloriIs Translocated into Epithelial Cells and Binds to SHP‐2 in Human Gastric Mucosa

Abstract

Recent experiments have indicated that CagA of Helicobacter pylori is injected into epithelial cells via the type IV secretion system and undergoes tyrosine phosphorylation in cells and that translocated CagA binds the SRC homology 2 domain-containing tyrosine phosphatase (SHP-2). We investigated these phenomena in in vivo human gastric mucosa. Tyrosine-phosphorylated CagA and CagA-coimmunoprecipitated SHP-2 were detected in gastric mucosa from H. pylori-positive patients with atrophic gastritis and in noncancerous tissues from H. pylori-positive patients with early gastric cancer. In contrast, CagA was not detected in gastric mucosa with either intestinal metaplasia or cancer. Our results provide the first evidence that CagA is translocated into the gastric epithelial cells, receives tyrosine phosphorylation, and binds SHP-2 in in vivo human gastric mucosa. Deregulation of SHP-2 by CagA may play a role in the acquisition of a cellular-transformed phenotype at a relatively early stage of multistep gastric carcinogenesis.

Helicobacter pylori CagA Induces Ras-independent Morphogenetic Response through SHP-2 Recruitment and Activation

“…Although the CagA-SHP-2 complex was originally demonstrated by transient expression of the cagA gene in AGS cells (22), it has also been detected in AGS cells infected with cagA-positive H. pylori (Fig. 1D) as well as in in vivo gastric mucosa from a patient with cagA-positive H. pylori infection (23). These findings exclude the possibility that the CagA-SHP-2 complex is detectable only when CagA is expressed by gene transfection.…”

Helicobacter pylori persistence: biology and disease

“…One substrate for the type IV system in H. pylori is the cagA product (30, 31, S21-S23), which is injected into epithelial cells, both in vitro (30, 31, S22, S23) and in vivo (32) (Figure 2). In many strains, the CagA protein contains tyrosinephosphorylation sites (30,31,33, S21-S23) that are recognized by the host cell Src kinase (34).…”

“…In many strains, the CagA protein contains tyrosinephosphorylation sites (30,31,33, S21-S23) that are recognized by the host cell Src kinase (34). Once phosphorylated, CagA interacts with SHP-2, a tyrosine phosphatase (35), which affects spreading, migration, and adhesion of epithelial cells (32). This phenomenon can be assessed in vitro by a change in epithelial cell morphology to the scattered, or "hummingbird," phenotype (31).…”

Helicobacter pylori CagA Phosphorylation Status Determines the gp130-activated SHP2/ERK and JAK/STAT Signal Transduction Pathways in Gastric Epithelial Cells

“…H. pylori injects the CagA protein into host gastric epithelial cells via a type IV secretion system (11-16). The injected CagA is tyrosine-phosphorylated by Src family protein-tyrosine kinases and binds SHP2 (Src homology 2 domain-containing Src homology tyrosine phosphatase) (17-21); the CagA-SHP2 complex has been detected in human gastric mucosa (22,23).The IL6/gp130/STAT3 (interleukin-6/glycoprotein 130/signal transducer and activation of transcription 3) pathway has been shown to play a role in the development of gastric cancer (24, 25). IL6 exerts its biological activities through the receptor subunit gp130 (26).…”