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

Archana Varadaraj, Laura M. Jenkins, Priyanka Singh, Anindya Chanda, John Snider, N. Y. Lee, Ayelet R. Amsalem-Zafran, Marcelo Ehrlich, Yoav I. Henis, Karthikeyan Mythreye

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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 transcriptionand 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.

Original languageEnglish (US)
Pages (from-to)1195-1207
Number of pages13
JournalMolecular biology of the cell
Volume28
Issue number9
DOIs
StatePublished - May 1 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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