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TGF-? triggers rapid fibrillogenesis via a novel T?RII-dependent fibronectin-trafficking mechanism.

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 ? (TGF-?) is an established regulator of ECM remodeling via transcriptional control of ECM proteins. Here we show that TGF-?, through increased FN trafficking in a transcription- and SMAD-independent manner, is a direct and rapid inducer of the fibrillogenesis required for TGF-?-induced cell migration. Whereas TGF-? signaling is dispensable for rapid fibrillogenesis, stable interactions between the cytoplasmic domain of the type II TGF-? receptor (T?RII) and the FN receptor (?5?1 integrin) are required. We find that, in response to TGF-?, cell surface-internalized FN is not degraded by the lysosome but instead undergoes recycling and incorporation into fibrils, a process dependent on T?RII. These findings are the first to show direct use of trafficked and recycled FN for fibrillogenesis, with a striking role for TGF-? 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.

SUBMITTER: Varadaraj A 

PROVIDER: S-EPMC5415016 | BioStudies | 2017-01-01

REPOSITORIES: biostudies

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