Abstract
In airway smooth muscle cells ligand binding to the seven-transmembrane endothelin and thrombin receptors stimulates cell growth. Rapid activation of the extracellular regulated kinase 2 and c-Jun NH2-terminal kinase groups of mitogen-activated protein kinases was also observed. The results demonstrate a novel mechanism of seven-transmembrane receptor signaling involving activation of the Jun kinase pathway. Receptor coupling to Jun kinase activation may involve heterotrimeric G proteins since the kinase was enzymatically activated in cells treated with aluminum fluoride. The activity of Raf-1, measured by immune complex kinase assay, revealed that platelet-derived growth factor and phorbol 12-myristate 13-acetate both stimulated Raf-1 activity, while thrombin and endothelin did not appreciably stimulate Raf-1. The data suggest that endothelin and thrombin stimulate Raf-1-independent mechanisms of mitogen-activated protein kinase activation. Endothelin- or thrombin-induced activation of mitogen-activated protein kinases was significantly inhibited by activation of cyclic AMP-dependent protein kinase by forskolin. Proliferation of airway smooth muscle cells, measured by incorporation of [3H]thymidine into DNA, was also greatly attenuated by forskolin.
Highlights
Threonine kinases encoded by the ERK2 and ERK1 genes, respectively, that are enzymatically activated by tyrosine and threonine phosphorylation in response to numerous different stimuli [5,6,7,8]
Pretreatment of the cells with forskolin, an agent that increases the catalytic activity of protein kinase (PKA), inhibited the ability of endothelin, thrombin, and PMA to activate the ERK2 MAP kinase (Fig. 1)
We have determined that stimulation of the endothelin or thrombin receptors in airway smooth muscle cells results in activation of both the MAP kinase and Jun kinase pathways, as measured by catalytic activity of the ERK2 and JNK1 kinases
Summary
Threonine kinases encoded by the ERK2 and ERK1 genes, respectively, that are enzymatically activated by tyrosine and threonine phosphorylation in response to numerous different stimuli [5,6,7,8]. The human JNK1 and JNK2 genes encode 46- and 55-kDa kinases, respectively, that are distantly related to the MAP kinases and are activated by phosphorylation on a single threonine and single tyrosine residue. While JNK activation is known to follow stimulation of the TNF-␣ receptor, as well as tyrosine kinase receptors such as the epidermal growth factor receptor, this report demonstrates that seven-transmembrane receptors activate the JNK subgroup of MAP kinases. Activation of these kinases is inhibited by forskolin, which increases the enzymatic activity of cyclic AMP-dependent protein kinase (PKA). The ability of endothelin and thrombin to induce the proliferation of ASM cells is inhibited by activating PKA, suggesting that activation of the ERK and JNK kinase cascades is an essential component of the proliferative effects of endothelin and thrombin
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