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Activated Src requires Cadherin-11, Rac, and gp130 for Stat3 activation and survival of mouse Balb/c3T3 fibroblasts

Hanad Adan1,2, Stephanie Guy3, Rozanne Arulanandam3

  • 1Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, K7L 3N6, Canada.

Cancer Gene Therapy
|April 12, 2022
PubMed

Insights

Cadherin engagement activates Rac GTPases and IL6 signaling, leading to Stat3 activation. However, activated Src downregulates cadherin-11, impacting gp130 levels and Stat3 signaling, revealing a crucial regulatory loop.

Area of Science:

  • Cellular biology
  • Molecular signaling
  • Cancer research

Background:

  • Cadherins mediate cell-cell adhesion and regulate intracellular signaling pathways.
  • Rac/Cdc42 GTPases are key regulators of cell growth, survival, and cytokine signaling.
  • Interleukin-6 (IL6) family cytokines and their receptor gp130 are crucial in immune responses and cell proliferation.

Purpose of the Study:

  • To investigate the role of activated Src in regulating IL6 family cytokine signaling and Stat3 activation.
  • To elucidate the interplay between Src, cadherin-11, gp130, and Stat3 in fibroblasts.
  • To understand the impact of Src-mediated downregulation of cadherin-11 on downstream signaling.

Main Methods:

  • Utilized mouse Balb/c3T3 fibroblasts.
  • Employed mutationally activated Src (Src527F) expression.
  • Assessed Rac GTPase levels, IL6 family cytokine secretion, gp130 activation, and Stat3 phosphorylation (Stat3-ptyr705).
  • Investigated the role of cadherin-11 in preserving gp130 levels and signaling.

Main Results:

  • Mutationally activated Src527F increased Rac levels, leading to IL6 family cytokine secretion and gp130 activation, subsequently increasing Stat3-ptyr705.
  • Cadherin-11 was found to be essential for maintaining gp130 levels for IL6 family signaling.
  • Activated Src527F quantitatively downregulated cadherin-11, thereby reducing gp130 signaling and Stat3-ptyr705 stimulation at high expression levels.
  • A critical balance between Src527F and cadherin-11 levels was identified as necessary for Stat3 activation.

Conclusions:

  • Established a novel regulatory loop involving Src, cadherin-11, gp130, and Stat3 activation.
  • Demonstrated that Src-mediated downregulation of cadherin-11 fine-tunes gp130/Stat3 signaling.
  • Highlighted the therapeutic potential of targeting this balance for controlling Stat3-dependent cellular processes.

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