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Am J Physiol Cell Physiol (November 29, 2006). doi:10.1152/ajpcell.00370.2006
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Submitted on July 7, 2006
Accepted on November 21, 2006

TGF{beta}-REGULATED COLLAGEN TYPE I ACCUMULATION: ROLE OF SRC-BASED SIGNALS

Rangnath Mishra1, Ling Zhu2, Richard Eckert2, and Michael S. Simonson3*

1 Medicine, Case Western Reserve University, Cleveland, Ohio, United States
2 Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, United States
3 Nephrology, Case Western Reserve University, Cleveland, Ohio, United States

* To whom correspondence should be addressed. E-mail: mss5{at}po.cwru.edu.

Transforming growth factor {beta} (TGF{beta}) stimulates myofibroblast transdifferentiation, leading to type I collagen accumulation and fibrosis. Here we investigated the function of Src in TGF{beta}-induced collagen I accumulation. In human mesangial cells, PTyr416 Src (activated Src) was 3.3-fold higher in TGF{beta}-treated cells than in controls. Src activation by TGF{beta} was blocked by rottlerin and by a dominant-negative mutant of protein kinase C{delta} (PKC{delta}), showing that TGF{beta} activates Src by a PKC{delta}-based mechanism. Pharmacological inhibitors and a dominant negative Src mutant prevented the increase in collagen type I secretion in cells exposed to TGF{beta}. Similarly, on-target Src siRNA prevented type I collagen secretion in response to TGF{beta}, but off-target siRNA complexes had no effect. It is well-established in mesangial cells that up-regulation of type I collagen by TGF{beta} requires extracellular signal-regulated kinase 1/2 (ERK1/2), and we found that activation of ERK1/2 by TGF{beta} requires Src. In conclusion, these results suggest that stimulation of collagen type I secretion by TGF{beta} requires a PKC{delta}-Src-ERK1/2 signaling motif.




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