title: S-nitrosylation at cysteine 498 of c-Src tyrosine kinase regulates nitric oxide-mediated cell invasion.
abstract: 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.
authors: From the Division of Cancer Biology, Nagoya University School of Medicine, Nagoya 466-8550, Japan.
authors: Mohammad Aminur
authors: MA
authors: Rahman
authors: From the Division of Cancer Biology, Nagoya University School of Medicine, Nagoya 466-8550, Japan. Electronic address: tsenga@med.nagoya-u.ac.jp.
authors: Takeshi
authors: T
authors: Senga
authors: From the Division of Cancer Biology, Nagoya University School of Medicine, Nagoya 466-8550, Japan.
authors: Satoko
authors: S
authors: Ito
authors: From the Division of Cancer Biology, Nagoya University School of Medicine, Nagoya 466-8550, Japan.
authors: Toshinori
authors: T
authors: Hyodo
authors: From the Division of Cancer Biology, Nagoya University School of Medicine, Nagoya 466-8550, Japan.
authors: Hitoki
authors: H
authors: Hasegawa
authors: From the Division of Cancer Biology, Nagoya University School of Medicine, Nagoya 466-8550, Japan. Electronic address: mhamagu@med.nagoya-u.ac.jp.
authors: Michinari
authors: M
authors: Hamaguchi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement; D002478:Cells, Cultured; D003545:Cysteine / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D015538:Nitrosation / Q000187:drug effects; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism; D051575:Proto-Oncogene Proteins c-yes / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D004958:Estradiol; D026423:S-Nitroso-N-Acetylpenicillamine; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D051575:Proto-Oncogene Proteins c-yes; C496639:Yes1 protein, mouse; D019061:src-Family Kinases; D003545:Cysteine