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Thrombin/Matrix Metalloproteinase-9-Dependent SK-N-SH Cell Migration is Mediated Through a PLC/PKC/MAPKs/NF-κB

Chien-Chung Yang1,2, Chih-Chung Lin3, Peter Tzu-Yu Chien1

  • 1Department of Physiology and Pharmacology and Health Ageing Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.

Molecular Neurobiology
|October 27, 2015
PubMed

Insights

Thrombin triggers matrix metalloproteinase-9 (MMP-9) expression and cell migration in SK-N-SH cells. This process involves a signaling cascade including Gq, protein kinase C (PKC), p38 MAPK, JNK1/2, and NF-κB activation.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Thrombin is known to activate inflammatory genes, including matrix metalloproteinases (MMPs).
  • Elevated MMP-9 expression is observed in neuroinflammatory diseases, suggesting its role in brain pathology.
  • The specific mechanisms of thrombin-induced MMP-9 expression in SK-N-SH cells were previously unknown.

Purpose of the Study:

  • To elucidate the signaling pathways involved in thrombin-induced MMP-9 expression and cell migration in SK-N-SH cells.
  • To investigate the role of Gq, protein kinase C (PKC) isoforms, p38 MAPK, JNK1/2, and NF-κB in this process.

Main Methods:

  • SK-N-SH cells were treated with thrombin.
  • MMP-9 expression and cell migration were assessed using gelatin zymography, Western blot, real-time PCR, and cell migration assays.
  • Mechanisms were analyzed using pharmacological inhibitors and small interfering RNA (siRNA) targeting specific signaling molecules.

Main Results:

  • Thrombin significantly increased proform MMP-9 expression and SK-N-SH cell migration.
  • Inhibitors of thrombin, Gq, PLC, PKCs (including PKCα, PKCβ, PKCδ), p38 MAPK, JNK1/2, and NF-κB attenuated thrombin's effects.
  • Thrombin-induced phosphorylation of PKCα/βII, PKCδ, p38 MAPK, JNK1/2, and p65 was blocked by specific inhibitors.
  • siRNA-mediated knockdown of Gq, PKC isoforms, p38, JNK1/2, IKKα/β, or p65 also inhibited thrombin-induced MMP-9 expression and migration.

Conclusions:

  • Thrombin activates MMP-9 expression and cell migration in SK-N-SH cells via a signaling pathway involving Gq, PLC, PKCs, p38 MAPK, JNK1/2, and NF-κB.
  • This pathway is crucial for the observed cellular responses to thrombin in this neuronal cell model.
Keywords:
Matrix metalloproteinase-9NeurodegenerationNeuronal cellsSignaling pathwayThrombin

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