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J. Biol. Chem., Vol. 281, Issue 13, 8806-8814, March 31, 2006

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Syk Tyrosine Kinase Mediates Epstein-Barr Virus Latent Membrane Protein 2A-induced Cell Migration in Epithelial Cells^*

Jean Lu¹, Wan-Hsin Lin¹, Shao-Yin Chen, Richard Longnecker², Shu-Chun Tsai, Chi-Long Chen^¶, and Ching-Hwa Tsai³

From the Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 10063, Taiwan, the Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 60611, and the ^¶Department of Pathology, College of Medicine, National Taiwan University, Taipei 10063, Taiwan

Although spleen tyrosine kinase (Syk) is known to be important in hematopoietic cell development, the roles of Syk in epithelial cells have not been well studied. Limited data suggest that Syk plays alternate roles in carcinogenesis under different circumstances. In breast cancer, Syk has been suggested to be a tumor suppressor. In contrast, Syk is essential for murine mammary tumor virus-mediated transformation. However, the roles of Syk in tumor migration are still largely unknown. Nasopharyngeal carcinoma, an unusually highly metastatic tumor, expresses Epstein-Barr virus LMP2A (latent membrane protein 2A) in most clinical specimens. Previously, we demonstrated LMP2A triggers epithelial cell migration. LMP2A contains an immunoreceptor tyrosine-based activation motif, which is important for Syk kinase activation in B cells. In this study, we explored whether Syk is important for LMP2A-mediated epithelial cell migration. We demonstrate that LMP2A expression can activate endogenous Syk activity. The activation requires the tyrosine residues in LMP2A ITAM but not YEEA motif, which is important for Syk activation by Lyn in B cells. LMP2A interacts with Syk as demonstrated by coimmunoprecipitation and confocal microscopy. Furthermore, LMP2A-induced cell migration is inhibited by a Syk inhibitor and short interfering RNA. Tyrosines 74 and 85 in the LMP2A immunoreceptor tyrosine-based activation motif are essential for both Syk activation and LMP2A-mediated cell migration, indicating the involvement of Syk in LMP2A-triggered cell migration. The LMP2A-Syk pathway may provide suitable drug targets for treatment of nasopharyngeal carcinoma.

Received for publication, July 6, 2005 , and in revised form, December 26, 2005.

^* 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.

¹ Both authors contributed equally to this work and should be considered as first authors.

² Supported by United State Public Health Service Grants CA62234, CA73507, and CA93444 from the NCI, National Institutes of Health.

³ Supported by National Science Council Grants NSC 93-3112-B-002-006 and NSC94-3112-B-002-021 and the National Health Research Institutes Grant NHRI-Ex94-9419BI. To whom correspondence should be addressed: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Rm. 714, Number 1, Section 1, Jen-Ai Road, Taipei, Taiwan. Tel.: 886-2-2312-3456, ext. 8298; Fax: 886-2-2391-5293; E-mail: chtsai{at}ha.mc.ntu.edu.tw.

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