Nuclear signaling by endothelin-1 requires Src protein-tyrosine kinases

In response to changes in vascular homeostasis, endothelial cells secrete endothelin-1 (ET-1), which in turn regulates gene expression and phenotype in underlying vascular cells. We characterized a nuclear signaling cascade in which Src protein-tyrosine kinases link the ET-1 receptor to induction of c-fos transcription. A dominant negative SrcK- kinase mutant blocked ET-1-stimulated c-fos transcription. Expression of the COOH-terminal Src kinase (Csk), which represses Src kinases, also blocked induction of c-fos transcription by ET-1. Activation of the c-fos promoter by ET-1 required both the CArG DNA sequence of the c-fos serum response element and the Ca2+/cAMP response element. In contrast, Src-induced c-fos transcription required only the CArG cis-element, demonstrating a divergence in signals regulating c-fos transcription. Thus, Src kinases contribute to a nuclear signaling cascade linking an ET-1 receptor to the CArG element of the c-fos serum response element. A Src-based pathway might play a more general role to propagate ET-1 nuclear signals that regulate cell growth and development. In addition, these results point to a widening role for nonreceptor protein-tyrosine kinases in propagating signals from G protein-coupled receptors.