Abstract
BackgroundHelicobacter pylori (H. pylori) infection affects cell survival signaling pathways including cell apoptosis and proliferation, which are considered risk factors for the development of gastric cancer when unregulated. In the present study, we investigated the effect of H. pylori infection on the phosphorylation state of 3-phosphoinositide-dependent kinase-1 (PDK-1), a master kinase that regulates phosphorylation of Akt (also known as protein kinase B, PKB) and cell survival. MethodsThe activity of PDK-1 was examined in human gastric epithelial cells incubated in the presence or absence of different H. pylori strains. In addition, the role of H. pylori type IV secretion system and the mechanism of H. pylori effect on PDK-1 activity was examined.ResultsIn the presence of H. pylori, phosphorylation of the activation loop (serine 241) PDK-1 was rapidly lost suggesting that dephosphorylation of PDK-1 is a target for H. pylori to modulate cell survival. The extent of dephosphorylation was strain dependent with H. pylori 60190 being the most effective. H. pylori infection of gastric epithelial cells resulted in altered phosphorylation and degradation of Akt, suggesting that PDK-1 dephosphorylation affects cell survival pathways and thereby may contribute to disease pathogenesis.ConclusionWe propose that dephosphorylation of PDK-1 and the resulting changes to Akt phosphorylation is one of the mechanisms by which infection with H. pylori alter the balance between apoptosis and cell proliferation and identify a host molecular mechanism regulated by H. pylori that ultimately contributes to carcinogenesis. Our studies therefore provide insights into one of the mechanisms by which H. pylori infection contributes to gastric cancer by regulating the activity of a cell survival signaling pathway.
Highlights
Helicobacter pylori (H. pylori) infection affects cell survival signaling pathways including cell apoptosis and proliferation, which are considered risk factors for the development of gastric cancer when unregulated
We identified Src and Grb2 as PDK1binding proteins through a proteomic screen (King, unpublished results), suggesting that phosphoinositide-dependent kinase-1 (PDK-1) activity may be regulated in response to H. pylori infection
We show that activation loop phosphorylation of PDK-1, which plays a central role in cell survival signaling pathways, is dysregulated in response to H. pylori infection
Summary
Helicobacter pylori (H. pylori) infection affects cell survival signaling pathways including cell apoptosis and proliferation, which are considered risk factors for the development of gastric cancer when unregulated. Several intracellular signaling pathways are activated upon H. pylori infection of host gastric epithelial cells [9, 10, 13,14,15,16,17,18,19]. CagA interaction with SHP2 phosphatase and the Src family of kinases of the host cell are examples of how H. pylori is thought to hijack intracellular signaling pathways and potentially contribute to cancer development [20]. We wanted to characterize gastric epithelial cellular signaling responses following H. pylori infection, with a focus on pro-survival signals from PDK-1, which has not been investigated in relation to H. pylori infection
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