Helicobacter pylori CagA phosphorylation-independent function in epithelial proliferation and inflammation.
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 beta-catenin and NF-kappaB 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.
Suzuki
Masato
M
Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Mimuro
Hitomi
H
Kiga
Kotaro
K
Fukumatsu
Makoto
M
Ishijima
Nozomi
N
Morikawa
Hanako
H
Nagai
Shigenori
S
Koyasu
Shigeo
S
Gilman
Robert H
RH
Kersulyte
Dangeruta
D
Berg
Douglas E
DE
Sasakawa
Chihiro
C
D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism / Q000502:physiology*; D001426:Bacterial Proteins / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D004848:Epithelium / Q000382:microbiology* / Q000473:pathology*; D016480:Helicobacter pylori / Q000502:physiology*; D006801:Humans; D007249:Inflammation; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D037521:Virulence Factors / Q000378:metabolism / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016328:NF-kappa B; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor; D037521:Virulence Factors; D051176:beta Catenin; C080866:cagA protein, Helicobacter pylori; C491743:MET protein, human