TGF-β triggers rapid fibrillogenesis via a novel TβRII-dependent fibronectin-trafficking mechanism

Mol Biol Cell. 2017 May 1;28(9):1195-1207. doi: 10.1091/mbc.E16-08-0601. Epub 2017 Mar 15.

Abstract

Fibronectin (FN) is a critical regulator of extracellular matrix (ECM) remodeling through its availability and stepwise polymerization for fibrillogenesis. Availability of FN is regulated by its synthesis and turnover, and fibrillogenesis is a multistep, integrin-dependent process essential for cell migration, proliferation, and tissue function. Transforming growth factor β (TGF-β) is an established regulator of ECM remodeling via transcriptional control of ECM proteins. Here we show that TGF-β, through increased FN trafficking in a transcription- and SMAD-independent manner, is a direct and rapid inducer of the fibrillogenesis required for TGF-β-induced cell migration. Whereas TGF-β signaling is dispensable for rapid fibrillogenesis, stable interactions between the cytoplasmic domain of the type II TGF-β receptor (TβRII) and the FN receptor (α5β1 integrin) are required. We find that, in response to TGF-β, cell surface-internalized FN is not degraded by the lysosome but instead undergoes recycling and incorporation into fibrils, a process dependent on TβRII. These findings are the first to show direct use of trafficked and recycled FN for fibrillogenesis, with a striking role for TGF-β in this process. Given the significant physiological consequences associated with FN availability and polymerization, our findings provide new insights into the regulation of fibrillogenesis for cellular homeostasis.

MeSH terms

  • Cell Membrane / metabolism
  • Cell Movement / physiology
  • Cells, Cultured
  • Extracellular Matrix / metabolism
  • Extracellular Matrix Proteins / metabolism
  • Fibroblasts / metabolism
  • Fibronectins / biosynthesis
  • Fibronectins / metabolism*
  • Humans
  • Integrin alpha5beta1 / metabolism
  • Protein Serine-Threonine Kinases / metabolism*
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism*

Substances

  • Extracellular Matrix Proteins
  • Fibronectins
  • Integrin alpha5beta1
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II