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 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.
Rahman
Mohammad Aminur
MA
From the Division of Cancer Biology, Nagoya University School of Medicine, Nagoya 466-8550, Japan.
Senga
Takeshi
T
From the Division of Cancer Biology, Nagoya University School of Medicine, Nagoya 466-8550, Japan. Electronic address: tsenga@med.nagoya-u.ac.jp.
Ito
Satoko
S
From the Division of Cancer Biology, Nagoya University School of Medicine, Nagoya 466-8550, Japan.
Hyodo
Toshinori
T
From the Division of Cancer Biology, Nagoya University School of Medicine, Nagoya 466-8550, Japan.
Hasegawa
Hitoki
H
From the Division of Cancer Biology, Nagoya University School of Medicine, Nagoya 466-8550, Japan.
Hamaguchi
Michinari
M
From the Division of Cancer Biology, Nagoya University School of Medicine, Nagoya 466-8550, Japan. Electronic address: mhamagu@med.nagoya-u.ac.jp.
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*
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