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Roads to Stat3 Paved with Cadherins

Hanad Adan1, Juliet Daniel1, Leda Raptis2

  • 1Department of Biology, McMaster University, Hamilton, ON L8S 4L8, Canada.

Cells
|August 26, 2022
PubMed

Insights

Cadherin engagement activates Rac/Cdc42 GTPases, promoting IL6 cytokine secretion and Stat3 activation. This pathway, involving cadherins, Rac, and gp130, is crucial for cell division and survival, with implications for cancer drug development.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Cadherins mediate cell-cell adhesion and influence intracellular signaling pathways.
  • Signal transducer and activator of transcription-3 (Stat3) is a key regulator of cell division and survival.
  • The interplay between cadherins, GTPases, and Stat3 in cellular processes is not fully understood.

Purpose of the Study:

  • To elucidate the role of cadherin engagement in the activation of Stat3 signaling.
  • To investigate the molecular mechanisms linking cadherins, Rac/Cdc42 GTPases, and IL6 family cytokines to Stat3.
  • To explore the potential therapeutic implications of the cadherin-Stat3 axis in cancer.

Main Methods:

  • Investigated the effect of cadherin engagement on Rac/Cdc42 GTPase activity and proteasomal degradation.
  • Assessed the impact of cadherin signaling on IL6 family cytokine secretion and gp130 receptor activation.
  • Analyzed Stat3 phosphorylation, dimerization, nuclear translocation, and target gene activation.
  • Examined the role of Src oncogene and caveolin-1 in modulating the cadherin-Stat3 pathway.

Main Results:

  • Cadherin engagement increases Rac/Cdc42 GTPase activity by inhibiting proteasomal degradation, leading to IL6 cytokine secretion and autocrine gp130 activation.
  • This cascade results in Stat3 phosphorylation, dimerization, nuclear translocation, and activation of genes involved in cell division and survival.
  • Src oncogene and caveolin-1 modulate this pathway, highlighting a critical balance between Src, cadherins, and gp130 for Stat3 activation.
  • Absence of cadherin engagement leads to low Stat3 activity, emphasizing the importance of cadherin-gp130 interaction for Stat3 signaling.

Conclusions:

  • Cadherin engagement is essential for Stat3 activation, primarily through the preservation of gp130 function and regulation of the Rac/gp130 axis.
  • A delicate balance between Src, cadherins, and IL6 signaling is required for optimal Stat3 activation.
  • The cadherin-Rac-gp130 pathway represents a conserved mechanism for Stat3 activation with significant implications for cancer biology and drug development.
Keywords:
FAKIL6SrcStat3cadherinscaveolin-1cell densitygp130rac1

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