Host SHP1 phosphatase antagonizes Helicobacter pylori CagA and can be downregulated by Epstein–Barr virus

Abstract

Most if not all gastric cancers are associated with chronic infection of the stomach mucosa with Helicobacter pylori cagA-positive strains(1-4). Approximately 10% of gastric cancers also harbour Epstein-Barr virus (EBV) in the cancer cells(5,6). Following delivery into gastric epithelial cells via type IV secretion(7,8), the cagA-encoded CagA protein undergoes tyrosine phosphorylation on the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs initially by Src family kinases (SFKs) and then by c-Abl(9,10). Tyrosine-phosphorylated CagA binds to the pro-oncogenic protein tyrosine phosphatase SHP2 and thereby deregulates the phosphatase activity(11,12), which has been considered to play an important role in gastric carcinogenesis(13). Here we show that the SHP2 homologue SHP1 interacts with CagA independently of the EPIYA motif. The interaction potentiates the phosphatase activity of SHP1 that dampens the oncogenic action of CagA by dephosphorylating the CagA EPIYA motifs. In vitro infection of gastric epithelial cells with EBV induces SHP1 promoter hypermethylation, which strengthens phosphorylation-dependent CagA action via epigenetic downregulation of SHP1 expression. Clinical specimens of EBV-positive gastric cancers also exhibit SHP1 hypermethylation with reduced SHP1 expression. The results reveal that SHP1 is the long-sought phosphatase that can antagonize CagA. Augmented H. pylori CagA activity, via SHP1 inhibition, might also contribute to the development of EBV-positive gastric cancer.

Dualistic Face of H.pylori and Some Herpes Viruses Co-Infection Observation from Clinical Practice

“…Both pathogens share similar patterns of cell signaling pathways leading to proliferation, increased cell survival, immune evasion. Recent paper by Saju et al [9] showed that host's SHP1 phosphatase antagonizes Helicobacter pylori CagA and can be down regulated by EpsteinBarr virus. In vitro infection of gastric epithelial cells with EBV induces SHP1 promoter hypermethylation, which strengthens phosphorylation-dependent CagA action via epigenetic down regulation of SHP1 expression [9].…”

“…Recent paper by Saju et al [9] showed that host's SHP1 phosphatase antagonizes Helicobacter pylori CagA and can be down regulated by EpsteinBarr virus. In vitro infection of gastric epithelial cells with EBV induces SHP1 promoter hypermethylation, which strengthens phosphorylation-dependent CagA action via epigenetic down regulation of SHP1 expression [9]. While H. pylori cause epigenetic silencing of tumour-suppressor genes to deregulate cellular pathways, EBV-positive tumors exhibit a widespread and distinctive DNA hypermethylation profile [10].…”

Pathogenic enablers — toxic relationships in the stomach

“…In addition to H. pylori , EBV, a ubiquitous human herpes virus with oncogenic potential, is associated with the development of gastric adenocarcinoma, and has been linked to ~9% of gastric cancer cases worldwide 6 . An exciting new study by Saju et al 7 now describes a paradigm of how a bacterium and a virus collaborate to potentially exacerbate a disease they can each cause independently.…”

“…Specifically, Saju et al 7 report that a host phosphatase, SHP1 (also known as tyrosine-protein phosphatase non-receptor type 6 or PTPN6), interacts with H. pylori -delivered CagA and functions as a negative regulator of CagA phosphorylation. Using a combination of transient CagA transfections and co-culture of viable H. pylori cag + strains with gastric epithelial cells, the researchers demonstrate that CagA forms a complex with SHP1, which was independent of CagA tyrosine phosphorylation status and did not involve CagA EPIYA phosphorylation motifs 7 .…”

“…Using a combination of transient CagA transfections and co-culture of viable H. pylori cag + strains with gastric epithelial cells, the researchers demonstrate that CagA forms a complex with SHP1, which was independent of CagA tyrosine phosphorylation status and did not involve CagA EPIYA phosphorylation motifs 7 . Glutathione S -transferase pull-down assays verified the direct interaction between CagA and SHP1, which required the N -terminal region of SHP1, and both the C -terminal and N -terminal regions of CagA 7 .…”