Arizona Health Sciences

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

TitleTGF-β triggers rapid fibrillogenesis via a novel TβRII-dependent fibronectin-trafficking mechanism.
Publication TypeJournal Article
Year of Publication2017
AuthorsVaradaraj A, Jenkins LM, Singh P, Chanda A, Snider J, Lee NY, Amsalem-Zafran AR, Ehrlich M, Henis YI, Mythreye K
JournalMol Biol Cell
Volume28
Issue9
Pagination1195-1207
Date Published2017 May 01
ISSN1939-4586
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.

DOI10.1091/mbc.E16-08-0601
Alternate JournalMol. Biol. Cell
PubMed ID28298487
PubMed Central IDPMC5415016
Grant ListP20 GM109091 / GM / NIGMS NIH HHS / United States
Faculty Member Reference: 
Nam Lee, Ph.D.