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S-nitrosylation at cysteine 498 of c-Src tyrosine kinase regulates nitric oxide-mediated cell invasion

Mohammad Aminur Rahman1, Takeshi Senga1, Satoko Ito1

  • 1From the Division of Cancer Biology, Nagoya University School of Medicine, Nagoya 466-8550, Japan.

The Journal of Biological Chemistry
|December 2, 2009
PubMed

Insights

Nitric oxide (NO) activates Src kinase activity by S-nitrosylation at Cys498, promoting cancer cell invasion and metastasis. This pathway is crucial for estrogen-induced breast cancer cell migration and invasion.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Nitric oxide (NO) is implicated in cancer progression, influencing cell invasion and metastasis.
  • Src family kinases, particularly c-Src, are known to promote cancer cell invasion and metastasis.
  • The precise mechanisms by which NO activates Src kinase activity remain largely unknown.

Purpose of the Study:

  • To elucidate the mechanism by which NO stimulates Src kinase activity.
  • To identify the specific site of NO-mediated modification on c-Src.
  • To investigate the role of this NO-Src pathway in estrogen-induced breast cancer cell behavior.

Main Methods:

  • Investigated the S-nitrosylation of c-Src at cysteine 498 (Cys(498)) upon NO stimulation.
  • Examined the functional significance of Cys(498) S-nitrosylation for c-Src kinase activity.
  • Studied the effect of beta-estradiol on NO production and c-Src activation in MCF7 breast cancer cells.
  • Assessed the role of NO-dependent c-Src activation in beta-estradiol-induced E-cadherin disruption and cell invasion.

Main Results:

  • NO directly stimulates c-Src kinase activity through S-nitrosylation at Cys(498).
  • Cys(498) is conserved in Src family kinases, with a corresponding cysteine in c-Yes also important for NO-mediated activation.
  • Beta-estradiol induces NO production in MCF7 cells, leading to S-nitrosylation and activation of c-Src at Cys(498).
  • Beta-estradiol-induced disruption of E-cadherin junctions and enhanced cell invasion are mediated by NO-dependent c-Src activation.

Conclusions:

  • Nitric oxide activates Src family kinases via S-nitrosylation of a conserved cysteine residue (Cys(498) in c-Src).
  • This NO-Src signaling pathway is a key mediator of estrogen-induced breast cancer cell proliferation, migration, invasion, and metastasis.
  • The findings reveal a novel mechanism linking NO and Src kinases in cancer progression.

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