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Mechanisms of transforming growth factor-beta receptor endocytosis and intracellular sorting differ between

J J Doré1, D Yao, M Edens

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

Molecular Biology of the Cell
|March 17, 2001
PubMed

Insights

Transforming growth factor-betas (TGF-beta) signaling pathways involve specific receptor residues that regulate endocytosis and cell response. Key mutations reveal differences in how mesenchymal and epithelial cells handle TGF-beta receptor trafficking.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Transforming growth factor-betas (TGF-beta) are crucial regulators of cell proliferation and differentiation.
  • TGF-beta exerts its effects through a receptor complex comprising type I and type II serine/threonine kinase receptors.
  • Cellular responses to TGF-beta are diverse, varying by cell type, and mediated by a single receptor complex.

Purpose of the Study:

  • To investigate the roles of specific amino acid residues in TGF-beta type I and II receptors in regulating ligand-mediated endocytosis and signaling.
  • To elucidate the mechanisms of TGF-beta receptor trafficking and signaling in fibroblasts and epithelial cells.
  • To identify key residues critical for TGF-beta receptor internalization, recycling, and down-regulation.

Main Methods:

  • Construction of chimeric receptors by fusing ligand-binding domains of the granulocyte/macrophage colony-stimulating factor receptor to TGF-beta receptor signaling domains.
  • Introduction of point mutations at specific residues (Y182, T200, Y249 in type I; K277, P525 in type II) within the TGF-beta receptor complex.
  • Analysis of endocytosis, signaling, and receptor down-regulation in response to TGF-beta stimulation in fibroblasts and epithelial cells.

Main Results:

  • Mutations at Y182 and Y249, within putative internalization motifs, did not affect TGF-beta receptor endocytosis or signaling.
  • Mutation of T200 to valine abolished TGF-beta signaling in both cell types and receptor down-regulation in fibroblasts.
  • Fibroblasts and epithelial cells constitutively internalize and recycle TGF-beta receptors in the absence of ligand.

Conclusions:

  • Specific amino acid residues, particularly T200 in the type I receptor, are critical for TGF-beta-mediated signaling and receptor regulation.
  • Ligand binding diverts heteromeric TGF-beta receptors from a default recycling pathway to one involving down-regulation and signaling.
  • Mesenchymal and epithelial cells exhibit fundamental differences in the endocytic sorting of TGF-beta receptors.

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