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J. Biol. Chem., Vol. 283, Issue 20, 13952-13963, May 16, 2008

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The β₁ 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 Allison¹, Bryan H. Bellaire^¶, Richard L. Ferrero, and James A. Cardelli²

From the Department of Microbiology and Immunology and the Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130, the Department of Microbiology, Monash University, Clayton 3800, Victoria, Australia, and the ^¶Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University of Science and Technology, Ames, Iowa 50011-1240

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, because 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, 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 60190cagA but not 60190cagE, demonstrating CagA-independent signaling critical for cell motility. A β₁ 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 β₁ integrin pathway.

Received for publication, January 11, 2008 , and in revised form, March 20, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant CA104242. The work performed in the laboratory of R. L. F. was supported in part by National Health and Medical Research Council of Australia Project Grant 334127 (to R. L. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–6.

¹ Supported by a postgraduate scholarship from the Faculty of Medicine, Nursing and Health Sciences and the Department of Microbiology.

² To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130. E-mail: jcarde{at}lsuhsc.edu.

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