癌症研究
EPH受体A2
生物
受体酪氨酸激酶
肿瘤进展
转移
酪氨酸激酶
血管生成
癌变
激酶
癌症
信号转导
细胞生物学
遗传学
作者
Wei Bin Fang,Dana M. Brantley-Sieders,Monica A. Parker,Alastair D. Reith,Jin Chen
出处
期刊:Oncogene
[Springer Nature]
日期:2005-08-15
卷期号:24 (53): 7859-7868
被引量:118
标识
DOI:10.1038/sj.onc.1208937
摘要
Receptor tyrosine kinases of the Eph family are upregulated in several different types of cancer. One family member in particular, the EphA2 receptor, has been linked to breast, prostate, lung and colon cancer, as well as melanoma. However, mechanisms by which EphA2 contributes to tumor progression are far from clear. In certain tumor cell lines, EphA2 receptor is underphosphorylated, raising the question of whether ligand-induced receptor phosphorylation and its kinase activity play a role in oncogenesis. To test directly the role of EphA2 receptor phosphorylation/kinase activity in tumor progression, we generated EphA2 receptor variants that were either lacking the cytoplasmic domain or carrying a point mutation that inhibits its kinase activity. Expression of these EphA2 mutants in breast cancer cells resulted in decreased tumor volume and increased tumor apoptosis in primary tumors. In addition, the numbers of lung metastases were significantly reduced in both experimental and spontaneous metastasis models. Reduced tumor volume and metastasis are not due to defects in tumor angiogenesis, as there is no significant difference in tumor vessel density between wild-type tumors and tumors expressing EphA2-signaling-defective mutants. In contrast, tumor cells expressing the EphA2 mutants are defective in RhoA GTPase activation and cell migration. Taken together, these results suggest that receptor phosphorylation and kinase activity of the EphA2 receptor, at least in part, contribute to tumor malignancy.
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