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TGFβ1 rapidly activates Src through a non-canonical redox mechanism

Hongqiao Zhang1, Henry Jay Forman2

  • 1Andrus Gerontology Center, Davis School of Gerontology, University of Southern California.

Free Radical Biology & Medicine
|October 14, 2015
PubMed

Insights

Transforming growth factor-β1 activates Src kinase via a redox-dependent mechanism, involving specific cysteine residues. This study reveals a novel pathway for Src activation by TGF-β1.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Signaling

Background:

  • Transforming growth factor-β1 (TGF-β1) regulates crucial cellular processes like epithelial-mesenchymal transition (EMT).
  • TGF-β1-mediated cellular functions are often regulated by the activation of Src kinase, a non-receptor tyrosine kinase.
  • The precise mechanism by which TGF-β1 activates Src remains largely undefined.

Purpose of the Study:

  • To elucidate the mechanism underlying TGF-β1-induced Src kinase activation.
  • To investigate the potential role of redox-dependent pathways in TGF-β1-mediated Src activation.
  • To identify specific residues within Src kinase involved in its activation by TGF-β1.

Main Methods:

  • Investigated Src phosphorylation at Tyr419 and Tyr530 following TGF-β1 exposure.
  • Utilized hydrogen peroxide (H2O2) measurements to assess oxidative stress.
  • Employed inhibitors like vanadate, GSH-ester, and catalase to probe signaling pathways.
  • Performed site-directed mutagenesis of cysteine residues in Src kinase to alanine (C/A).

Main Results:

  • TGF-β1 exposure increased both pTyr419 Src and pTyr530 Src, deviating from the canonical activation model.
  • TGF-β1 transiently elevated extracellular H2O2 levels.
  • Antioxidants (GSH-ester, catalase) blocked TGF-β1-induced Src activation.
  • Mutations of Cys248, Cys277, Cys490, and Cys501 abrogated TGF-β1-mediated Src activation without affecting Src stability.

Conclusions:

  • TGF-β1 activates Src kinase through a redox-dependent mechanism.
  • Specific cysteine residues (248, 277, 490, 501) are critical for TGF-β1-induced Src activation.
  • This study uncovers a novel redox-based pathway for Src activation by TGF-β1, impacting cellular processes like EMT.

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