TGF-beta-regulated collagen type I accumulation: role of Src-based signals.
Transforming growth factor-beta (TGF-beta) stimulates myofibroblast transdifferentiation, leading to type I collagen accumulation and fibrosis. 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 Cdelta (PKCdelta), showing that TGF-beta activates Src by a PKCdelta-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 small interference RNA (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 upregulation 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 PKCdelta-Src-ERK1/2 signaling motif.
Mishra
Rangnath
R
Division of Nephrology, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Zhu
Ling
L
Eckert
Richard L
RL
Simonson
Michael S
MS
D000098:Acetophenones / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D002454:Cell Differentiation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D050527:Mesangial Cells / Q000378:metabolism*; D009154:Mutation; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
D000098:Acetophenones; D001578:Benzopyrans; D024042:Collagen Type I; D016212:Transforming Growth Factor beta; C085746:rottlerin; D019061:src-Family Kinases; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases