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RECEPTORS AND SIGNAL TRANSDUCTION

Effects of _1D-adrenergic receptors on shedding of biologically active EGF in freshly isolated lacrimal gland epithelial cells

¹Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston; ²Tufts University School of Dental Medicine, Boston, Massachusetts; and ³Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio

Submitted 13 January 2006 ; accepted in final form 25 May 2006

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 ₁-adrenergic receptors (ARs), namely, _1B- and _1D-ARs. _1D-ARs mediate phenylephrine (an ₁-adrenergic agonist)-induced protein secretion and activation of p42/p44 MAPK, because the _1D-AR inhibitor BMY-7378, but not the _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, ₁-adrenergic agonists activate the _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.

epidermal growth factor ectodomain shedding; protein secretion; signal transduction

This article has been cited by other articles:

				C. Funaki, R. R. Hodges, and D. A. Dartt Role of cAMP inhibition of p44/p42 mitogen-activated protein kinase in potentiation of protein secretion in rat lacrimal gland Am J Physiol Cell Physiol, November 1, 2007; 293(5): C1551 - C1560. [Abstract] [Full Text] [PDF]

				A. C. Snider and K. E. Meier Receptor transactivation cascades. Focus on "Effects of {alpha}1D-adrenergic receptors on shedding of biologically active EGF in freshly isolated lacrimal gland epithelial cells" Am J Physiol Cell Physiol, January 1, 2007; 292(1): C1 - C3. [Full Text] [PDF]