Helicobacter pylori modulates host cell survival regulation through the serine-threonine kinase, 3-phosphoinositide dependent kinase 1 (PDK-1).
BACKGROUND
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. 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.


METHODS
The 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.


RESULTS
In 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.


CONCLUSIONS
We 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.
Pediatric Diabetes Research Center, University of California, La Jolla, San Diego, CA, 92093, USA. chking@ad.ucsd.edu.
Charles C
CC
King
Department of Medicine, University of California, La Jolla, San Diego, CA, 92093, USA. mobonyo@ucsd.edu.
Marygorret
M
Obonyo
D002460:Cell Line; D002470:Cell Survival; D004847:Epithelial Cells / Q000382:microbiology* / Q000502:physiology*; D016480:Helicobacter pylori / Q000254:growth & development*; D054884:Host-Pathogen Interactions; D006801:Humans; D010716:Phosphatidylinositols; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
D010716:Phosphatidylinositols; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt