Par1-substrates responsible for CagA-mediated pathogenesis of Helicobacter pylori Gastritis and gastric carcinoma, the second leading cause of cancer-related deaths in the world, have been linked to infection with Helicobacter pylori, a bacterium that colonizes the gastric mucosa. H. pylori strains that harbor a gene called cytotoxin-associated gene A (CagA) are more virulent and present a much higher cancer risk for their host than strains that lack CagA and recently the toxin has been shown to function as an oncoene in mice. CagA induces loss of cell polarity, increased cell migration and apoptosis of gastric epithelial cells and promotes aberrant growth signals by activating the Ras-MAP-cascade. Recently, we and others have identified the serine/threonine kinase Par1 as a CagA-target responsible for epithelial polarity defects associated with H. pylori pathology. The challenge at hand now is to delineate the CagA signaling pathway(s) downstream of Par1. Although a known polarity determinant, Par1-substrates that mediate mammalian epithelial polarity have not yet been discerned. In preliminary experiments, we have developed an unbiased Par1 substrate screen that enabled us to identify 63 putative substrates, most of them novel, and their precise Par1b phosphorylation sites in epithelial cells. Our goal is to evaluate the contribution of all validated substrates to CagA-mediated loss of epithelial cell shape and polarity. Since we have determined that Par1b inhibits proliferation and negatively regulates mTOR signaling in epithelial cells, we will also evaluate whether Par1b substrates are relevant for the effects of CagA on proliferation. In a two-tiered approach we will first characterize Par1b substrates downstream of CagA in the kidney-derived epithelial model cell line MDCK and subsequently validate their significance for H. pylori infection of primary human gastric epithelia

Public Health Relevance

Gastric carcinoma is the second leading cause of cancer-related deaths in the world and the fourth most common cancer with approximately 930,000 new cases diagnosed worldwide annually. The disease has been linked to infection with Helicobacter pylori, a bacterium that colonizes the gastric mucosa. Our project is designed to identify novel signaling- mechanisms by which H. pylori leads to tumorigenesis of the stomach epithelium.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA160790-01A1
Application #
8372334
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Daschner, Phillip J
Project Start
2012-07-10
Project End
2017-04-30
Budget Start
2012-07-10
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$511,917
Indirect Cost
$182,258
Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Müsch, Anne (2014) The unique polarity phenotype of hepatocytes. Exp Cell Res 328:276-83