TGF-beta-regulated collagen type I accumulation: role of Src-based signals |
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Authors: | Mishra Rangnath Zhu Ling Eckert Richard L Simonson Michael S |
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Institution: | Division of Nephrology, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. |
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Abstract: | 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 TGF- was blocked by rottlerin and by a dominant negative mutant of protein kinase C (PKC ), showing that TGF- activates 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 TGF- requires extracellular signal-regulated kinase 1/2 (ERK1/2), and we found that activation of ERK1/2 by TGF- requires Src. In conclusion, these results suggest that stimulation of collagen type I secretion by TGF- requires a PKC -Src-ERK1/2 signaling motif. mesangial cells; fibrosis; glomerulus; transforming growth factor-![beta](http://ajpcell.physiology.org/math/beta.gif) |
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