title: Tensin 1 Is Essential for Myofibroblast Differentiation and Extracellular Matrix Formation.
abstract: Myofibroblasts, the primary effector cells that mediate matrix remodeling during pulmonary fibrosis, rapidly assemble an extracellular fibronectin matrix. Tensin (TNS) 1 is a key component of specialized cellular adhesions (fibrillar adhesions) that bind to extracellular fibronectin fibrils. We hypothesized that TNS1 may play a role in modulating myofibroblast-mediated matrix formation. We found that TNS1 expression is increased in fibroblastic foci from lungs with idiopathic pulmonary fibrosis. Transforming growth factor (TGF)-β profoundly up-regulates TNS1 expression with kinetics that parallel the expression of the myofibroblast marker, smooth muscle α-actin. TGF-β-induced TNS1 expression is dependent on signaling through the TGF-β receptor 1 and is Rho coiled-coiled kinase/actin/megakaryoblastic leukemia-1/serum response factor dependent. Small interfering RNA-mediated knockdown of TNS1 disrupted TGF-β-induced myofibroblast differentiation, without affecting TGF-β/Smad signaling. In contrast, loss of TNS1 resulted in disruption of focal adhesion kinase phosphorylation, focal adhesion formation, and actin stress fiber development. Finally, TNS1 was essential for the formation of fibrillar adhesions and the assembly of nascent fibronectin and collagen matrix in myofibroblasts. In summary, our data show that TNS1 is a novel megakaryoblastic leukemia-1-dependent gene that is induced during pulmonary fibrosis. TNS1 plays an essential role in TGF-β-induced myofibroblast differentiation and myofibroblast-mediated formation of extracellular fibronectin and collagen matrix. Targeted disruption of TNS1 and associated signaling may provide an avenue to inhibit tissue fibrosis.
authors.affiliation: 1 Department of Medicine and.
authors.forename: Ksenija
authors.initials: K
authors.lastname: Bernau
authors.affiliation: 1 Department of Medicine and.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Torr
authors.affiliation: 2 Biostatistics and Medical Informatics, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Evans
authors.affiliation: 1 Department of Medicine and.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Aoki
authors.affiliation: 1 Department of Medicine and.
authors.forename: Caitlyn R
authors.initials: CR
authors.lastname: Ngam
authors.affiliation: 1 Department of Medicine and.
authors.forename: Nathan
authors.identifier: 0000-0002-5732-4589
authors.initials: N
authors.lastname: Sandbo
mesh_terms: D000199:Actins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D058105:Polymerization / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D000070876:Tensins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D000070876:Tensins; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020930:MAP Kinase Kinase Kinases; C433243:MAP3K9 protein, human; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: extracellular matrix; fibrillar adhesion; megakaryoblastic leukemia-1; myofibroblast; tensin 1