S-Nitrosylation at Cysteine 498 of c-Src Tyrosine Kinase Regulates Nitric Oxide-mediated Cell Invasion

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 can...

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Bibliographic Details
Published in:The Journal of biological chemistry 2010-02, Vol.285 (6), p.3806-3814
Main Authors: Rahman, Mohammad Aminur, Senga, Takeshi, Ito, Satoko, Hyodo, Toshinori, Hasegawa, Hitoki, Hamaguchi, Michinari
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Blotting, Western
Breast Cancer
Cadherins - metabolism
Cell Adhesion - drug effects
Cell Line, Tumor
Cell Movement
Cell/Migration
Cells, Cultured
Cysteine - metabolism
Estradiol - pharmacology
Humans
Mechanisms of Signal Transduction
Mice
Mice, Knockout
Microscopy, Fluorescence
Molecular Sequence Data
Mutation
Nitric Oxide
Nitric Oxide - metabolism
Nitric Oxide Donors - pharmacology
Nitrosation - drug effects
Proto-Oncogene Proteins c-fyn - genetics
Proto-Oncogene Proteins c-fyn - metabolism
Proto-Oncogene Proteins c-yes - genetics
Proto-Oncogene Proteins c-yes - metabolism
RNA Interference
S-Nitroso-N-Acetylpenicillamine - pharmacology
S-nitrosylation
Sequence Homology, Amino Acid
Signal Transduction
Signal Transduction/Phosphotyrosine
Signal Transduction/Protein Kinases/Tyrosine
Src
src-Family Kinases - genetics
src-Family Kinases - metabolism
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Summary: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 (Cys498) to stimulate its kinase activity. Cys498 is conserved among Src family kinases, and Cys506 of c-Yes, which corresponds to Cys498 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, β-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 β-estradiol stimulation was mediated by the S-nitrosylation of Cys498. In addition, we report that disruption of E-cadherin junctions and enhancement of cell invasion by β-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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M109.059782