| セッション情報 |
Helicobacter Pylori Infection:Basic and Clinical Topics
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| タイトル |
IF2-2 H. pylori-mediated Gastric Carcinogenesis ； A New Paradigm of Cancer Development
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| 演者 |
Masanori Hatakeyama（Department of MicrobiologyGraduate School of MedicineThe University of TokyoJapan） |
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| 抄録 |
Chronic infection with Helicobac亡er pylori cagA－positive strains is the strongest risk factor fbr the devel－opment of gastric carcinomathe fourth most common cancer and the second leading cause of cancer－related death worldwide． The cagA 一encoded CagA protein is a 120 N 145－kDa proteinwhich is deliveredinto gastric epithelial cells via a type IV secretion system． Upon delivery into gastric epithelial cellsCagAis localized to the inner face of the plasma membranewhere it undergoes tyrosine phosphorylation at theEPIYA motifs by Src family kinases （SFKs）． lnside the hoist cellsCagA acts as a pathogenic protein scaf－fold／hub by promiscuously interacting with a variety of ho＄t proteins． Among theseSHP2 tyrosine phos－phatase is of particular interest because gainDf－function mutation of PTPNI Ia gene encoding SHP2isassociated with a variety of human malignancies． The CagA－SHP2 interaction deregulates the SHP2 phos－phatase activityresulting in the aberrant activation of pro－mitogenic／proDncogenic Erk MAP kinase sig－naling． CagA also binds to the polarity－regulating serine／threonine kinase PAR I／MARK independent ofEPIYA phosphorylation and causes j unctional and polarity defects by inhibiting the kinase activity． Pro－miscuous interaction of CagA with host proteins indicates that the bacterial effector acts to promote celltransformation． lndeedoncogenic potential of H． pylori CagA has been demonstrated by the observationthat transgenic mice systemically expressing wild－type CagA spontaneously develop gastrointestinal andhematological malignanciesNotablyhowevertransgenic mice expressing phospho－resistant CagA didnot develop any abnormalities including tumors． These observations point to a critical role of CagA－SHP 2interactionwhich requires CagA tyrosine phosphorylationin in vivo tumorigenesis． |
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