TGF- -regulated collagen type I accumulation: role of Src-based signals

Mishra R, Zhu L, Eckert RL, Simonson MS. TGF-regulated collagen type I accumulation: role of Src-based signals. Am J Physiol Cell Physiol 292: C1361–C1369, 2007. First published November 29, 2006; doi:10.1152/ajpcell.00370.2006.—Transforming growth factor(TGF) stimulates myofibroblast transdifferentiation, leading to type I collagen accumulation and fibrosis. We investigated the function of Src in TGF-induced collagen I accumulation. In human mesangial cells, PTyr416 Src (activated Src) was 3.3-fold higher in TGF-treated cells than in controls. Src activation by TGFwas blocked by rottlerin and by a dominant negative mutant of protein kinase C (PKC ), showing that TGFactivates Src by a PKC based mechanism. Pharmacological inhibitors and a dominant negative Src mutant prevented the increase in collagen type I secretion in cells exposed to TGF. Similarly, on-target Src small interference RNA (siRNA) prevented type I collagen secretion in response to TGF, but off-target siRNA complexes had no effect. It is well established in mesangial cells that upregulation of type I collagen by TGFrequires extracellular signal-regulated kinase 1/2 (ERK1/2), and we found that activation of ERK1/2 by TGFrequires Src. In conclusion, these results suggest that stimulation of collagen type I secretion by TGFrequires a PKC -Src-ERK1/2 signaling motif.