A common pathophysiological finding in obstructive airway diseases such as asthma is remodeling of the airway, including increased proliferation of the airway smooth muscle cells. Several mitogens such as thrombin, endothelin, and platelet derived growth factor (PDGF) are known to induce proliferation of airway smooth muscle (ASM) cells in culture. However, the molecular pathways by which these agonists stimulate the growth of ASM cells is largely unknown. Our preliminary data regarding the ability of endothelin and thrombin to activate key intracellular signal transduction pathways by distinct mechanisms in ASM cells, suggests that activation of these kinase pathways may be physiologically significantly. The ASM mitogens endothelin and thrombin activate both the mitogen activated protein (MAP) kinase pathway and the Jun kinase pathway in ASM cells. The activation of the MAP kinase pathway by both thrombin and endothelin, but not PDGF requires the presence of protein kinase C (KC), suggesting this kinase may be regulating the coupling of the thrombin and endothelin receptors to the MAP kinase pathway. The ability of thrombin and endothelin to activate both the MAP kinase and Jun kinase pathways is significantly inhibited by activation of the cAMP-dependent protein kinase (PKA). This finding suggests PKA phosphorylation negatively regulates key intermediaries of both the MAP kinase and Jun kinase pathways. Experiments have been designed to test the hypothesis that the proliferative effects of thrombin and endothelin are mediated by activation of the MAP kinases and Jun kinases in thrombin and endothelin- induced proliferation by specifically blocking their activation through the use of dominant negative mutants of key components of both pathways. In addition, the endothelin receptor appears to activate the MAP kinases via a novel, currently unidentified kinase(s). Such novel activators of the MAP kinase pathway will be identified and cloned.
| Vichi, P; Whelchel, A; Knot, H et al. (1999) Endothelin-stimulated ERK activation in airway smooth-muscle cells requires calcium influx and Raf activation. Am J Respir Cell Mol Biol 20:99-105 |
| Vichi, P; Whelchel, A; Posada, J (1999) Transmembrane helix 7 of the endothelin B receptor regulates downstream signaling. J Biol Chem 274:10331-8 |
| Whelchel, A; Evans, J; Posada, J (1997) Inhibition of ERK activation attenuates endothelin-stimulated airway smooth muscle cell proliferation. Am J Respir Cell Mol Biol 16:589-96 |
| Shapiro, P; Absher, P M; Posada, J P et al. (1997) Activation of ERK and JNK1 MAP kinases in cultured lung tissue. Am J Physiol 273:L459-67 |
| Aquilla, E; Whelchel, A; Knot, H J et al. (1996) Activation of multiple mitogen-activated protein kinase signal transduction pathways by the endothelin B receptor requires the cytoplasmic tail. J Biol Chem 271:31572-9 |
