TY - JOUR
T1 - Helicobacter pylori CagA Phosphorylation-Independent Function in Epithelial Proliferation and Inflammation
AU - Suzuki, Masato
AU - Mimuro, Hitomi
AU - Kiga, Kotaro
AU - Fukumatsu, Makoto
AU - Ishijima, Nozomi
AU - Morikawa, Hanako
AU - Nagai, Shigenori
AU - Koyasu, Shigeo
AU - Gilman, Robert H.
AU - Kersulyte, Dangeruta
AU - Berg, Douglas E.
AU - Sasakawa, Chihiro
N1 - Funding Information:
We thank all the members of our laboratory for their helpful discussions and technical advice. This work was supported by a Grant-in-Aid for Young Scientists (19790314); a Grand-in-Aid for Scientific Research (20229006); a Contract Research Fund for the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases; the Strategic Cooperation to Control Emerging and Reemerging Infections funded by the Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT); and the Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Agency (JST). D.E.B. and R.H.G. are supported by grants from the NIH (RO1 DK63041, T53 1007646, and D43TW006581). The authors have no conflicting financial interests.
PY - 2009/1/22
Y1 - 2009/1/22
N2 - CagA, a major virulence factor of Helicobacter pylori (Hp), is delivered into gastric epithelial cells and exists in phosphorylated and nonphosphorylated forms. The biological activity of the phosphorylated form is well established; however, function(s) of the nonphosphorylated form remain elusive. Here, we report that a conserved motif in the C-terminal region of CagA, which is distinct from the EPIYA motifs used for phosphorylation and which we designate CRPIA (conserved repeat responsible for phosphorylation-independent activity), plays pivotal roles in Hp pathogenesis. The CRPIA motif in nonphosphorylated CagA was involved in interacting with activated Met, the hepatocyte growth factor receptor, leading to the sustained activation of phosphatidylinositol 3-kinase/Akt signaling in response to Hp infection. This in turn led to the activation of β-catenin and NF-κB signaling, which promote proliferation and inflammation, respectively. Thus, nonphosphorylated CagA activity contributes to the epithelial proliferative and proinflammatory responses associated with development of chronic gastritis and gastric cancer.
AB - CagA, a major virulence factor of Helicobacter pylori (Hp), is delivered into gastric epithelial cells and exists in phosphorylated and nonphosphorylated forms. The biological activity of the phosphorylated form is well established; however, function(s) of the nonphosphorylated form remain elusive. Here, we report that a conserved motif in the C-terminal region of CagA, which is distinct from the EPIYA motifs used for phosphorylation and which we designate CRPIA (conserved repeat responsible for phosphorylation-independent activity), plays pivotal roles in Hp pathogenesis. The CRPIA motif in nonphosphorylated CagA was involved in interacting with activated Met, the hepatocyte growth factor receptor, leading to the sustained activation of phosphatidylinositol 3-kinase/Akt signaling in response to Hp infection. This in turn led to the activation of β-catenin and NF-κB signaling, which promote proliferation and inflammation, respectively. Thus, nonphosphorylated CagA activity contributes to the epithelial proliferative and proinflammatory responses associated with development of chronic gastritis and gastric cancer.
KW - MICROBIO
KW - SIGNALING
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U2 - 10.1016/j.chom.2008.11.010
DO - 10.1016/j.chom.2008.11.010
M3 - Article
C2 - 19154985
AN - SCOPUS:58249083314
SN - 1931-3128
VL - 5
SP - 23
EP - 34
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 1
ER -