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Type II transforming growth factor-beta receptor recycling is dependent upon the clathrin adaptor protein Dab2

Sumedha G Penheiter1, Raman Deep Singh, Claire E Repellin

  • 1Thoracic Diseases Research Unit, Department of Biochemistry and Molecular Biology and Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN 55905, USA.

Molecular Biology of the Cell
|October 1, 2010
PubMed

Insights

Disabled-2 (Dab2) is crucial for transforming growth factor-beta (TGF-β) receptor recycling in mesenchymal cells. Loss of Dab2 impairs TGF-β receptor trafficking and signaling, impacting cell phenotypes.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • Transforming growth factor-beta (TGF-β) signaling is mediated by heteromeric complexes of TGF-β ligands and transmembrane serine/threonine kinase receptors.
  • While TGF-β signaling regulation is well-studied, the endocytic and trafficking pathways of its receptor subunits remain less understood.
  • Disabled-2 (Dab2) is a clathrin-associated sorting protein implicated in various cellular processes.

Purpose of the Study:

  • To investigate the role of Disabled-2 (Dab2) in the endocytosis and trafficking of TGF-β receptor subunits.
  • To elucidate the impact of Dab2 on TGF-β receptor itinerary and downstream signaling in mesenchymal cells.

Main Methods:

  • Small interfering RNA (siRNA) was used to knockdown Dab2 expression in mesenchymal cells.
  • Endocytosis and recycling of various cargo, including TGF-β receptors, were assessed.
  • Endosomal morphology and trafficking were analyzed using early endosomal antigen 1 (EEA1) as a marker.
  • Smad2 phosphorylation, a key downstream signaling event, was measured.

Main Results:

  • Dab2 knockdown did not affect the internalization of clathrin-dependent or -independent cargo.
  • TGF-β receptor recycling was significantly abrogated in Dab2-deficient cells.
  • Loss of Dab2 led to enlarged early endosomes, indicating impaired trafficking to the endosomal recycling compartment.
  • Smad2 phosphorylation was diminished in cells lacking Dab2.

Conclusions:

  • Dab2 functions as a multifunctional adaptor protein in mesenchymal cells.
  • Dab2 is essential for the proper recycling of TGF-β receptors from early endosomes.
  • Dab2 plays a critical role in maintaining TGF-β receptor trafficking and subsequent Smad2 phosphorylation, influencing TGF-β signaling outcomes.

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