title: TGF-β triggers rapid fibrillogenesis via a novel TβRII-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 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208.
authors.forename: Archana
authors.initials: A
authors.lastname: Varadaraj
authors.affiliation: Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Jenkins
authors.affiliation: Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Singh
authors.affiliation: Department of Environmental Health Sciences, University of South Carolina, Columbia, SC 29201.
authors.forename: Anindya
authors.initials: A
authors.lastname: Chanda
authors.affiliation: Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208.
authors.forename: John
authors.initials: J
authors.lastname: Snider
authors.affiliation: Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus, OH 43210.
authors.forename: N Y
authors.initials: NY
authors.lastname: Lee
authors.affiliation: Department of Neurobiology, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ayelet R
authors.initials: AR
authors.lastname: Amsalem-Zafran
authors.affiliation: Department of Cell Research and Immunology, Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Ehrlich
authors.affiliation: Department of Neurobiology, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Yoav I
authors.initials: YI
authors.lastname: Henis
authors.affiliation: Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208 mythreye@sc.edu.|Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208.
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Mythreye
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D039081:Integrin alpha5beta1; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II