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Int. J. Mol. Sci. 2014, 15(11), 21433-21454; doi:10.3390/ijms151121433

Epidermal Growth Factor Receptor Transactivation Is Required for Mitogen-Activated Protein Kinase Activation by Muscarinic Acetylcholine Receptors in HaCaT Keratinocytes

Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, D-35392 Giessen, Germany
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Received: 11 October 2014 / Revised: 13 November 2014 / Accepted: 17 November 2014 / Published: 21 November 2014
(This article belongs to the Collection G Protein-Coupled Receptor Signaling and Regulation)
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Abstract

Non-neuronal acetylcholine plays a substantial role in the human skin by influencing adhesion, migration, proliferation and differentiation of keratinocytes. These processes are regulated by the Mitogen-Activated Protein (MAP) kinase cascade. Here we show that in HaCaT keratinocytes all five muscarinic receptor subtypes are expressed, but M1 and M3 are the subtypes involved in mitogenic signaling. Stimulation with the cholinergic agonist carbachol leads to activation of the MAP kinase extracellular signal regulated kinase, together with the protein kinase Akt. The activation is fully dependent on the transactivation of the epidermal growth factor receptor (EGFR), which even appears to be the sole pathway for the muscarinic receptors to facilitate MAP kinase activation in HaCaT cells. The transactivation pathway involves a triple-membrane-passing process, based on activation of matrix metalloproteases, and extracellular ligand release; whereas phosphatidylinositol 3-kinase, Src family kinases or protein kinase C do not appear to be involved in MAP kinase activation. Furthermore, phosphorylation, ubiquitination and endocytosis of the EGF receptor after cholinergic transactivation are different from that induced by a direct stimulation with EGF, suggesting that ligands other than EGF itself mediate the cholinergic transactivation. View Full-Text
Keywords: G protein coupled receptor; epidermal growth factor; acetylcholine; muscarinic receptor; transactivation; mitogen-activated protein kinase; keratinocytes; matrix metalloprotease G protein coupled receptor; epidermal growth factor; acetylcholine; muscarinic receptor; transactivation; mitogen-activated protein kinase; keratinocytes; matrix metalloprotease
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Ockenga, W.; Kühne, S.; Bocksberger, S.; Banning, A.; Tikkanen, R. Epidermal Growth Factor Receptor Transactivation Is Required for Mitogen-Activated Protein Kinase Activation by Muscarinic Acetylcholine Receptors in HaCaT Keratinocytes. Int. J. Mol. Sci. 2014, 15, 21433-21454.

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