Myofibroblast Differentiation by Transforming Growth Factor-β1 Is Dependent on Cell Adhesion and Integrin Signaling via Focal Adhesion Kinase*

By V. Thannickal, Daniel Y. Lee, E. White, Zongbin Cui, José M. Larios, R. Chacon, J. Horowitz, R. Day, P. Thomas. Journal of Biological Chemistry, 2003

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Myofibroblast differentiation and activation by transforming growth factor-β1 (TGF-β1) is a critical event in the pathogenesis of human fibrotic diseases, but regulatory mechanisms for this effect are unclear. In this report, we demonstrate that stable expression of the myofibroblast phenotype requires both TGF-β1and adhesion-dependent signals. TGF-β1-induced myofibroblast differentiation of lung fibroblasts is blocked in non-adherent cells despite the preservation of TGF-β receptor(s)-mediated signaling of Smad2 phosphorylation. TGF-β1 induces tyrosine phosphorylation of focal adhesion kinase (FAK) including that of its autophosphorylation site, Tyr-397, an effect that is dependent on cell adhesion and is delayed relative to early Smad signaling. Pharmacologic inhibition of FAK or expression of kinase-deficient FAK, mutated by substituting Tyr-397 with Phe, inhibit TGF-β1-induced α-smooth muscle actin expression, stress fiber formation, and cellular hypertrophy. Basal expression of α-smooth muscle actin is elevated in cells grown on fibronectin-coated dishes but is decreased on laminin and poly-d-lysine, a non-integrin binding polypeptide. TGF-β1 up-regulates expression of integrins and fibronectin, an effect that is associated with autophosphorylation/activation of FAK. Thus, a safer and more effective therapeutic strategy for fibrotic diseases characterized by persistent myofibroblast activation may be to target this integrin/FAK pathway while not interfering with tumor-suppressive functions of TGF-β1/Smad signaling.

Subfields: Cell Biology, Immunology and Allergy, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/573a9a8f8c3024838bb7f58009608d4a77a15f5d

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In Cell Biology

1. Nikolaos G. Frangogiannis
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Citations in the corpus

• TGF-beta and fibrosis in different organs - molecular pathway imprints. (2009, background): “Recently, an involvement of the focal adhesion kinase (FAK) has been established in myofibroblast differentiation and in remodeling of the connective tissue following stimulation with TGF [24,25].”
• TGF-β signaling in fibrosis (2011, background): “2010a), but also involves FAK, JNK, TAK, and PI3 kinase/Akt pathways (Bakin et al. 2000; Thannickal et al. 2003; Liu et al. 2007; Shi-wen et al. 2009).”
• All in the CCN family: essential matricellular signaling modulators emerge from the bunker (2006, result): “Induction of -SMA by TGF has been shown to be FAK-, adhesionand integrin-dependent (Thannickal et al., 2003), which supports the notion that integrins are functional receptors for CCN2.”
• Formation and function of the myofibroblast during tissue repair. (2007, background): “Consistently, phosphorylated focal adhesion kinase is central in the adhesion-dependent differentiation of cultured lung (Thannickal et al., 2003) and scleroderma myofibroblast (Mimura et al., 2005).”