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Cell Cycle Signaling by Endothelin-1 Requires Src Nonreceptor Protein Tyrosine Kinase

Division of Nephrology and Hypertension, Department of Medicine, School of Medicine, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio

Cross-talk between G protein-coupled receptors and protein tyrosine kinases is well established, but the phenotypic consequences of these signaling interactions are not completely understood. To investigate the role of Src family kinases in mitogenic signaling by G protein-coupled receptors, we used genetic and pharmacological inhibition of Src to study cell growth in response to endothelin-1. We found that dominant-negative Src and COOH-terminal Src kinase blocked mesangial cell growth in response to endothelin-1, whereas growth induced by v-Ras was unaffected. Endothelin-1-induced cell growth was blocked by the pharmacological Src antagonist 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) but not by the inactive analog 4-amino-7-phenylpyrazol[3,4-d]pyrimidine. RNA interference knockdown of Src with on-target but not with off-target small interfering RNAs also inhibited growth in cells treated with endothelin-1. Dominant-negative Src prevented growth in cells activated by platelet-derived growth factor alone or in combination with endothelin-1, which suggests that Src integrates mitogenic signals from diverse classes of cell surface receptors. To further explore the role of Src in mitogenic signaling by G protein-coupled receptors, we sought to determine whether endothelin-1 induced cyclin D1 by a Src-based mechanism. We found that endothelin-1 increased cyclin D1 protein, which was blocked by preincubation with the Src antagonist PP2 and with the protein kinase C antagonist bisindolylmaleimide I. These results provide evidence for a Src- and protein kinase C-based pathway of mitogenic signaling by endothelin-1 receptors that involves cyclin D1.

Address correspondence to: Dr. Michael S. Simonson, Department of Medicine, Division of Nephrology, Biomedical Research Bldg., Rm. 427, Case Western Reserve University, 2109 Adelbert Rd., Cleveland, OH 44106. E-mail: mss5{at}po.cwru.edu

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