Cross‐talk between ERK MAP kinase and Smad‐signaling pathways enhances TGF‐β dependent responses in human mesangial cells

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Abstract
SPECIFIC AIMSTo determine the mechanism by which ERK activity enhances TGF-β-induced collagen expression in human mesangial cells, the effects of ERK inhibition on Smad signaling were evaluated. Based on our findings that suggest differential phosphorylation of sequences in receptor-regulated Smads (R-Smads), roles for different phospho-acceptor sites in R-Smad were evaluated using site-specific mutated Smad3 constructs.PRINCIPAL FINDINGS1. TGF-β induction of Smad3 transcriptional activity is decreased by ERK inhibitionPreviously we reported that TGF-β1 activates human mesangial cell extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK), but not p38 MAP kinase. Further, TGF-β stimulation of p3TP-Lux, a construct that contains TGF-β-responsive elements and AP-1 consensus sites derived from a portion of the type 1 plasminogen activator inhibitor promoter, is decreased by cotransfected ERK1 dominant negative mutant construct in mesangial cells. To rule out the possibility that the i...
Funding Information
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK49362)