Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites

Abstract

Helicobacter pylori is a causative agent of gastritis and peptic ulcer. cagA ؉ H. pylori strains are more virulent than cagA ؊ strains and are associated with gastric carcinoma. The cagA gene product, CagA, is injected by the bacterium into gastric epithelial cells and subsequently undergoes tyrosine phosphorylation. The phosphorylated CagA specifically binds SHP-2 phosphatase, activates the phosphatase activity, and thereby induces morphological transformation of cells. CagA proteins of most Western H. pylori isolates have a 34-amino acid sequence that variably repeats among different strains. Here, we show that the repeat sequence contains a tyrosine phosphorylation site. CagA proteins having more repeats were found to undergo greater tyrosine phosphorylation, to exhibit increased SHP-2 binding, and to induce greater morphological changes. In contrast, predominant CagA proteins specified by H. pylori strains isolated in East Asia, where gastric carcinoma is prevalent, had a distinct tyrosine phosphorylation sequence at the region corresponding to the repeat sequence of Western CagA. This East Asian-specific sequence conferred stronger SHP-2 binding and morphologically transforming activities to Western CagA. Finally, a critical amino acid residue that determines SHP-2 binding activity among different CagA proteins was identified. Our results indicate that the potential of individual CagA to perturb host-cell functions is determined by the degree of SHP-2 binding activity, which depends in turn on the number and sequences of tyrosine phosphorylation sites. The presence of distinctly structured CagA proteins in Western and East Asian H. pylori isolates may underlie the strikingly different incidences of gastric carcinoma in these two geographic areas.

Association between serum pepsinogens and polymorphismof PTPN11 encoding SHP‐2 among Helicobacter pylori seropositive Japanese

“…SHP-2 binding with CagA is via the typical SH2 domain-phosphotyrosine interaction. 38 Through complex formation, SHP-2 is converted from the catalytically inactive form to the active form. Inactivation of either SH2 domain abolishes the CagA-binding activity of SHP-2, indicating that both of the SHP-2 domains are required for the stable complex formation with CagA.…”

“…Inactivation of either SH2 domain abolishes the CagA-binding activity of SHP-2, indicating that both of the SHP-2 domains are required for the stable complex formation with CagA. 38 The G/A polymorphism in the PTPN11 may influence the interaction with CagA through inactivation of either SH2 domain, resulting in attenuated signal transmission to the downstream CagAAESHP-2 complex and subsequent Erk reduction. If Erk is not activated, the abnormal proliferation and movement of gastric epithelial cells, potentially leading to gastric atrophy and neoplasia, would be reduced.…”

Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA

“…The tyrosine phosphorylation site of CagA is characterized by the Glu-Pro-IleTyr-Ala (EPIYA) motif, which is present in multiple numbers in the carboxy-terminal polymorphic region (EPIYA-repeat region) of the protein (Higashi et al, 2002a, b). On the basis of sequences flanking the EPIYA motifs, four distinct EPIYA segments, EPIYA-A, -B, -C and -D, each of which contains a single EPIYA motif, have been identified in the EPIYA-repeat region (Higashi et al, 2002b(Higashi et al, , 2005Naito et al, 2006) ( Figure 1). The representative CagA proteins of Western H. pylori isolates (Western CagA) possess the EPIYA-A and EPIYA-B segments followed by the EPIYA-C segment.…”

Risk of cagA DNA in H. Pylori Patients

“…H. pylori do not perform bacteremia and septicemia but are capable of cagA protein secretion and cagA genome integration into host cells. Thus risk of integration of cagA genome in to the host cell chromosome and induction of antibodies against it may correlate with several disorders (15)(16)(17)(18). This research indicates that from 18 positive cagA samples, 12 samples had high TG & Chol titers and cardiac disorder predisposition.…”