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.

Nesprin‐2G knockout fibroblasts exhibit reduced migration, changes in focal adhesion composition, and reduced ability to generate traction forces

“…Paxillin recruitment to FAs is mediated by vinculin, which also functions as both a structural and signaling component of the FA (Rahman et al, 2016;Subauste et al, 2004;Ziegler, Liddington, & Critchley, 2006). Tensin-1 is a structural protein within the FA which interacts with other FA proteins to mediate anchorage of actin stress fibers to each FA (Bernau et al, 2016;Zhao et al, 2016). Zyxin is reported to be the "last" protein incorporated into a mature FA and stabilizes FA-actin interaction (Zaidel-Bar et al, 2004).…”

Presence of meniscus tear alters gene expression profile of anterior cruciate ligament tears

“…Hence it is likely that lower expression of TNS1 following a combined injury suggest less matrix synthesis and thus less repair potential. This is supported by the fact that TNS1 also plays an essential role in TGF‐β‐induced myofibroblast differentiation and formation of extracellular fibronectin and collagen matrix . While historically known as myocyte enhancer factor 2D, global knockout of MEF2D does not impair muscle regeneration .…”

“…Among this, some genes have been known to play a role in ligament injury, matrix organization and OA. TNS1 (tensin 1), a key component of focal adhesion, is involved in cytoskeleton organization and is required for myofibroblast differentiation and extracellular matrix (ECM) formation . Hence it is likely that lower expression of TNS1 following a combined injury suggest less matrix synthesis and thus less repair potential.…”

MaTAR25LncRNA Regulates theTensin1Gene to Impact Breast Cancer Progression

“…Tns1 has been shown to localize to focal adhesions and to assist in mediating signaling between the extracellular matrix and the actin cytoskeleton to impact cell movement and proliferation (35, 36). Several reports have shown that loss of Tns1 can cause a decrease in cell motility in many cell types (46–48), and Tns1 has also been shown to be involved in epithelial-mesenchymal transition (EMT) of cancer cells (49). The general relationship between the expression of Tns1 and different stages/subtypes of breast cancer has been unclear.…”