Tropomyosin 2.1 collaborates with fibronectin to promote TGF-ß1-induced contraction of human lung fibroblasts.

Many lung diseases are characterized by fibrosis, leading to impaired tissue patency and reduced lung function. Development of fibrotic tissue depends on two-way interaction between the cells and the extra-cellular matrix (ECM). Concentration-dependent increased stiffening of the ECM is sensed by the cells, which in turn increases intracellular contraction and pulling on the matrix causing matrix reorganization and further stiffening. It is generally accepted that the inflammatory cytokine growth factor ß1 (TGF-ß1) is a major driver of lung fibrosis through the stimulation of ECM production. However, TGF-ß1 also regulates the expression of members of the tropomyosin (Tm) family of actin associating proteins that mediate ECM reorganization through intracellular-generated forces. Thus, TGF-ß1 may mediate the bi-directional signaling between cells and the ECM that promotes tissue fibrosis. Using combinations of cytokine stimulation, mRNA, protein profiling and cellular contractility assays with human lung fibroblasts, we show that concomitant induction of key Tm isoforms and ECM by TGF-ß1, significantly accelerates fibrotic phenotypes. Knocking down Tpm2.1 reduces fibroblast-mediated collagen gel contraction. Collectively, the data suggest combined ECM secretion and actin cytoskeleton contractility primes the tissue for enhanced fibrosis. Our study suggests that Tms are at the nexus of inflammation and tissue stiffening. Small molecules targeting specific Tm isoforms have recently been designed; thus targeting Tpm2.1 may represent a novel therapeutic target in lung fibrosis.

Cataloguing the phosphorylation sites of tristetraprolin (TTP): Functional implications for inflammatory diseases.

Tristetraprolin (TTP) is a destabilizing mRNA binding protein known to regulate gene expression of a wide variety of targets, including those that control inflammation. TTP expression, regulation and function is controlled by phosphorylation. While the importance of key serine (S) sites (S52 and S178 in mice and S186 in humans) has been recognized, other sites on the hyperphosphorylated TTP protein have more recently emerged as playing an important role in regulating cellular signalling and downstream functions of TTP. In order to propel investigation of TTP and fully exploit its potential as a drug target in inflammatory disease, this review will catalogue TTP phosphorylation sites in both the murine and human TTP protein, the known and unknown roles and functions of these sites, the kinases and phosphatases that act upon TTP and overview methodological approaches to increase our knowledge of this important protein regulated by phosphorylation.