Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 291, Issue 5, Pages C946-C956Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00014.2006
Keywords
epidermal growth factor ectodomain shedding; protein secretion; signal transduction
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Funding
- NEI NIH HHS [R01 EY006177, EY06177] Funding Source: Medline
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Transactivation of EGF receptors by G protein-coupled receptors is a well-known phenomenon. This process involves the ectodomain shedding of growth factors in the EGF family by matrix metalloproteinases. However, many of these studies employ transformed and/or cultured cells that overexpress labeled growth factors. In addition, few studies have shown that EGF itself is the growth factor that is shed and is responsible for transactivation of the EGF receptor. In this study, we show that freshly isolated, nontransformed lacrimal gland acini express two of the three known alpha(1)-adrenergic receptors (ARs), namely, alpha(1B)-and alpha(1D)-ARs. alpha(1D)-ARs mediate phenylephrine (an alpha(1)-adrenergic agonist)-induced protein secretion and activation of p42/p44 MAPK, because the alpha(1D)-AR inhibitor BMY-7378, but not the alpha(1A)-AR inhibitor 5-methylurapidil, inhibits these processes. Activation of p42/p44 MAPK occurs through transactivation of the EGF receptor, which is inhibited by the matrix metalloproteinase ADAM17 inhibitor TAPI-1. In addition, phenylephrine caused the shedding of EGF from freshly isolated acini into the buffer. Incubation of freshly isolated cells with conditioned buffer from cells treated with phenylephrine resulted in activation of the EGF receptor and p42/p44 MAPK. The EGF receptor inhibitor AG1478 and an EGF-neutralizing antibody blocked this activation of p42/p44 MAPK. We conclude that in freshly isolated lacrimal gland acini, alpha(1)-adrenergic agonists activate the alpha(1D)-AR to stimulate protein secretion and the ectodomain shedding of EGF to transactivate the EGF receptor, potentially via ADAM17, which activates p42/p44 MAPK to negatively modulate protein secretion.
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