The β1 Integrin Activates JNK Independent of CagA, and JNK Activation Is Required for Helicobacter pylori CagA+-induced Motility of Gastric Cancer Cells

• Published in: The Journal of biological chemistry Vol. 283; no. 20; p. 13952
• Main Authors: Jared L. Snider, Cody Allison, Bryan H. Bellaire, Richard L. Ferrero, James A. Cardelli
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 16.05.2008
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M800289200

The Helicobacter pylori CagA protein is translocated into gastric epithelial cells through a t ype IV s ecretion s ystem (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, because strains 60190Δ cagA or 60190Δ cagE (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, because JNK inhibition blocked paxillin Tyr-118 phosphorylation, and paxillin expression knockdown completely abrogated bacteria-induced motility. Furthermore, JNK and paxillin Tyr-118 were activated by 60190Δ cagA but not 60190Δ cagE , demonstrating CagA-independent signaling critical for cell motility. A β 1 integrin-blocking antibody significantly inhibited JNK and paxillin Tyr-118 phosphorylation and cell scattering, demonstrating that CagA-independent signaling required for cell motility occurs through β 1. The requirement of both Src and focal adhesion kinase for signaling and motility further suggests 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 promotes cell motility through the β 1 integrin pathway.