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The integrin-coupled signaling adaptor p130Cas suppresses Smad3 function in transforming growth factor-beta signaling

Wook Kim1, Yong Seok Kang, Jin Soo Kim

  • 1Cell Dynamics Research Center and Bioimaging Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea.

Molecular Biology of the Cell
|March 7, 2008
PubMed

Insights

Integrin signaling counteracts transforming growth factor-beta (TGF-β)-induced cell growth inhibition through p130Cas. This interaction reduces Smad3 phosphorylation, facilitating cell cycle progression and offering insights into TGF-β resistance.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • Integrin and growth factor receptor signaling cooperate during cell cycle progression.
  • The cross-talk between integrin and transforming growth factor-beta (TGF-β) signaling pathways is not well understood.
  • TGF-β signaling typically inhibits cell growth and promotes cell cycle arrest.

Purpose of the Study:

  • To investigate the interplay between integrin signaling and TGF-β signaling.
  • To elucidate the role of p130Cas (Crk-associated substrate, 130 kDa) in mediating the effects of integrin on TGF-β signaling.
  • To understand the mechanism by which integrin signaling influences TGF-β-induced growth inhibition.

Main Methods:

  • Utilized cell adhesion assays on fibronectin and laminin.
  • Performed loss and gain of function studies for p130Cas.
  • Analyzed Smad3 phosphorylation, p15 and p21 expression, and cell cycle progression.

Main Results:

  • Integrin signaling counteracts TGF-β-induced growth inhibition.
  • p130Cas mediates the inhibitory effect of integrin signaling on TGF-β-induced Smad3 phosphorylation.
  • Loss of p130Cas abrogates the counteraction of TGF-β effects by integrin signaling.
  • Tyrosine-phosphorylated p130Cas binds to Smad3, reducing its phosphorylation, leading to decreased p15 and p21 expression and promoting cell cycle progression.

Conclusions:

  • Integrin signaling, via p130Cas, antagonizes TGF-β-mediated growth arrest.
  • p130Cas acts as a crucial mediator in the cross-talk between integrin and TGF-β/Smad signaling pathways.
  • The p130Cas-mediated regulation of TGF-β/Smad signaling provides a mechanism for resistance to TGF-β-induced growth inhibition.

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