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

R Mishra, L Zhu, RL Eckert… - American Journal of …, 2007 - journals.physiology.org
R Mishra, L Zhu, RL Eckert, MS Simonson
American Journal of Physiology-Cell Physiology, 2007journals.physiology.org
Transforming growth factor-β (TGF-β) stimulates myofibroblast transdifferentiation, leading to
type I collagen accumulation and fibrosis. We investigated the function of Src in TGF-β-
induced collagen I accumulation. In human mesangial cells, PTyr416 Src (activated Src) was
3.3-fold higher in TGF-β-treated cells than in controls. Src activation by TGF-β was blocked
by rottlerin and by a dominant negative mutant of protein kinase Cδ (PKCδ), showing that
TGF-β activates Src by a PKCδ-based mechanism. Pharmacological inhibitors and a …
Transforming growth factor-β (TGF-β) stimulates myofibroblast transdifferentiation, leading to type I collagen accumulation and fibrosis. We investigated the function of Src in TGF-β-induced collagen I accumulation. In human mesangial cells, PTyr416 Src (activated Src) was 3.3-fold higher in TGF-β-treated cells than in controls. Src activation by TGF-β was blocked by rottlerin and by a dominant negative mutant of protein kinase Cδ (PKCδ), showing that TGF-β activates Src by a PKCδ-based mechanism. Pharmacological inhibitors and a dominant negative Src mutant prevented the increase in collagen type I secretion in cells exposed to TGF-β. Similarly, on-target Src small interference RNA (siRNA) prevented type I collagen secretion in response to TGF-β, but off-target siRNA complexes had no effect. It is well established in mesangial cells that upregulation of type I collagen by TGF-β requires extracellular signal-regulated kinase 1/2 (ERK1/2), and we found that activation of ERK1/2 by TGF-β requires Src. In conclusion, these results suggest that stimulation of collagen type I secretion by TGF-β requires a PKCδ-Src-ERK1/2 signaling motif.
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