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Dab2 inhibits the cholesterol-dependent activation of JNK by TGF-β

Keren E Shapira1, Tal Hirschhorn2, Lior Barzilay2

  • 1Department of Neurobiology, Tel Aviv University, Tel Aviv 69978, Israel.

Molecular Biology of the Cell
|March 21, 2014
PubMed

Insights

Disabled-2 (Dab2) protein restricts TGF-β receptor mobility and enhances its endocytosis, negatively regulating JNK pathway activation. This mechanism balances TGF-β signaling via Smad and JNK pathways.

Area of Science:

  • Cell biology
  • Molecular signaling
  • Protein interactions

Background:

  • Transforming growth factor-β (TGF-β) signaling pathways are crucial for cellular processes but can be dysregulated in diseases.
  • Receptor localization within cell membranes influences signaling outcomes.
  • The role of disabled-2 (Dab2) in TGF-β signaling regulation remained unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which Dab2 modulates TGF-β signaling.
  • To investigate the impact of Dab2 on the localization and trafficking of the TGF-β type I receptor (TβRI).
  • To determine how Dab2 influences distinct TGF-β signaling outputs.

Main Methods:

  • Biophysical studies on TβRI lateral mobility and endocytosis.
  • TGF-β induced phosphoprotein signaling assays.
  • Small interfering RNA (siRNA) mediated knockdown and overexpression of Dab2.
  • Cholesterol depletion experiments.

Main Results:

  • Dab2 interacts with TβRI, restricting its lateral diffusion and promoting clathrin-mediated endocytosis.
  • Dab2 negatively regulates TGF-β-induced c-Jun N-terminal kinase (JNK) activation.
  • Smad pathway activation by TGF-β is not affected by Dab2 levels.
  • Cholesterol depletion disrupts JNK activation by TGF-β in Dab2-deficient cells.

Conclusions:

  • Dab2 acts as a critical regulator of TβRI membrane domain localization.
  • Dab2 balances TGF-β signaling by differentially affecting Smad and JNK pathways.
  • These findings provide a molecular basis for Dab2's role in TGF-β signal transduction.

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