Lu Jean, Lin Wan-Hsin, Chen Shao-Yin, Longnecker Richard, Tsai Shu-Chun, Chen Chi-Long, Tsai Ching-Hwa
Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 10063, Taiwan.
J Biol Chem. 2006 Mar 31;281(13):8806-14. doi: 10.1074/jbc.M507305200. Epub 2006 Jan 23.
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.
尽管已知脾酪氨酸激酶（Syk）在造血细胞发育中很重要，但Syk在上皮细胞中的作用尚未得到充分研究。有限的数据表明，Syk在不同情况下的致癌作用有所不同。在乳腺癌中，Syk被认为是一种肿瘤抑制因子。相反，Syk对于鼠乳腺肿瘤病毒介导的转化至关重要。然而，Syk在肿瘤迁移中的作用仍然很大程度上未知。鼻咽癌是一种异常高转移性肿瘤，在大多数临床标本中表达爱泼斯坦 - 巴尔病毒LMP2A（潜伏膜蛋白2A）。此前，我们证明LMP2A可触发上皮细胞迁移。LMP2A包含一个基于免疫受体酪氨酸的激活基序，这对于B细胞中Syk激酶的激活很重要。在本研究中，我们探讨了Syk对于LMP2A介导的上皮细胞迁移是否重要。我们证明LMP2A的表达可以激活内源性Syk活性。这种激活需要LMP2A免疫受体酪氨酸激活基序中的酪氨酸残基，但不需要YEEA基序，后者对B细胞中Lyn激活Syk很重要。通过免疫共沉淀和共聚焦显微镜证实LMP2A与Syk相互作用。此外，Syk抑制剂和短发夹RNA可抑制LMP2A诱导的细胞迁移。LMP2A免疫受体酪氨酸激活基序中的酪氨酸74和85对于Syk激活和LMP2A介导的细胞迁移都至关重要，表明Syk参与了LMP2A触发的细胞迁移。LMP2A - Syk途径可能为鼻咽癌的治疗提供合适的药物靶点。
