期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 285, 期 6, 页码 3806-3814出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.059782
关键词
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资金
- Ministry of Education, Science, Culture and Technology of Japan
Nitric oxide (NO) plays a pivotal role in tumorigenesis, particularly with relation to cancer cell invasion and metastasis. NO can reversibly couple to cysteine thiols to form an S-nitrosothiol, which regulates the enzymatic activities of target proteins. c-Src is a tyrosine kinase that promotes cancer cell invasion and metastasis. Interestingly, c-Src can be activated by NO stimulation. However, mechanisms by which NO stimulates Src kinase activity have not been elucidated. We report here that NO causes S-nitrosylation of c-Src at cysteine 498 (Cys(498)) to stimulate its kinase activity. Cys(498) is conserved among Src family kinases, and Cys(506) of c-Yes, which corresponds to Cys(498) of c-Src, was also important for the NO-mediated activation of c-Yes. Estrogens may work synergistically with NO to induce the proliferation and migration of many kinds of breast cancer cells. For example, beta-estradiol induces the expression of endothelial nitric synthase and production of NO in MCF7 cells. We found that activation of c-Src in MCF7 cells by beta-estradiol stimulation was mediated by the S-nitrosylation of Cys(498). In addition, we report that disruption of E-cadherin junctions and enhancement of cell invasion by beta-estradiol stimulation was mediated by NO-dependent activation of c-Src. These results identify a novel signaling pathway that links NO and Src family kinases to cancer cell invasion and metastasis.
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