MECHANISMS OF SIGNAL TRANSDUCTION
Myofibroblast Differentiation by Transforming Growth Factor-ॆ1 Is Dependent on Cell Adhesion and Integrin Signaling via Focal Adhesion Kinase*

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Myofibroblast differentiation and activation by transforming growth factor-ॆ1 (TGF-ॆ1) 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-ॆ1and adhesion-dependent signals. TGF-ॆ1-induced myofibroblast differentiation of lung fibroblasts is blocked in non-adherent cells despite the preservation of TGF-ॆ receptor(s)-mediated signaling of Smad2 phosphorylation. TGF-ॆ1 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-ॆ1-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-ॆ1 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-ॆ1/Smad signaling.

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Published, JBC Papers in Press, January 16, 2003, DOI 10.1074/jbc.M208544200

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This work was supported by Grant HL-67967 from the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked 舠advertisement舡 in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.