Focal Adhesion Kinase: A Key Mediator of Transforming Growth Factor Beta Signaling in Fibroblasts

Significance: There is no effective drug therapy for scarring and fibrotic disease. The cytokine transforming growth factor beta (TGF-beta) promotes tissue repair, but its excessive action can lead to over exuberant scarring and fibrotic disease. However, owing to the multifunctional nature of TGF-beta, broad targeting of the canonical Smad-TGF-beta signaling pathway in vivo is likely to have unintended, deleterious consequences. Recent Advances: (1) The myofibroblast is the essential cell type that mediates tissue repair and fibrosis. (2) TGF-beta is an essential contributor to myofibroblast differentiation and activity. (3) TGF-beta selectively promotes tissue repair and fibrosis via the noncanonical focal adhesion kinase (FAK) pathway; FAK mediates myofibroblast differentiation, and hence may represent a novel intervention point for drugs treating fibrotic disease. Critical Issues: Excessive scarring (e.g., in hypertrophic scars, keloids, and scleroderma) is characterized by enhanced TGF-beta signaling and is a major clinical problem. Drugs that selectively and effectively control the profibrotic action of TGF-beta is therefore of clinical relevance. Future Directions: FAK inhibition may represent a novel therapy for scarring disorders.