The ?1 integrin activates JNK independent of CagA, and JNK activation is required for Helicobacter pylori CagA+-induced motility of gastric cancer cells

Jared L Snider, Cody Charles Allison, Bryan H Bellaire, Richard Louis Ferrero, James A Cardelli

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50 Citations (Scopus)

Abstract

The Helicobacter pylori CagA protein is translocated into gastric epithelial cells through a type IV secretion system (TFSS), and published studies suggest CagA is critical for H. pylori-associated carcinogenesis. CagA is thought to be necessary and sufficient to induce the motogenic response observed in response to CagA+ strains, as CagA interacts with proteins involved in adhesion and motility. We report that H. pylori strain 60190 stimulated AGS cell motility through a CagA- and TFSS-dependent mechanism, since strains 60190cagA or 60190cagE (TFSS-defective) did not increase motility. The JNK pathway is critical for H. pylori-dependent cell motility, as inhibition using SP600125 (JNK1/2/3 inhibitor) or a JNK2/3-specific inhibitor blocked motility. JNK mediates H. pylori-induced cell motility by activating paxillin, since JNK inhibition blocked paxillin(Y118) phosphorylation, and paxillin expression knockdown completely abrogated bacterial-induced motility. Furthermore, JNK and paxillin(Y118) were activated by 60190cagA but not 60190cagE, demonstrating CagA-independent signaling critical for cell motility. A ss1 integrin-blocking antibody significantly inhibited JNK and paxillin(Y118) phosphorylation and cell scattering, demonstrating that CagA-independent signaling required for cell motility occurs through ss1. The requirement of both Src and FAK for signaling and motility further suggest the importance of integrin signaling in H. pylori-induced cell motility. Finally, we show that JNK activation occurs independent of known upstream kinases and signaling molecules, including Nod1, Cdc42, Rac1, MKK4, and MKK7, which demonstrates novel signaling leading to JNK activation. We report for the first time that H. pylori mediates CagA-independent signaling that promote cell motility through the ss1 integrin pathway.
Original languageEnglish
Pages (from-to)13952 - 13963
Number of pages12
JournalJournal of Biological Chemistry
Volume283
Issue number20
Publication statusPublished - 2008

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