1. Neurotrophins induce neuregulin release through protein kinase Cdelta activation.
- Author
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Esper RM and Loeb JA
- Subjects
- Acetophenones pharmacology, Amino Acid Sequence, Animals, Avian Proteins genetics, Benzopyrans pharmacology, Blotting, Western, CHO Cells, Cells, Cultured, Chick Embryo, Chickens, Cricetinae, Cricetulus, Enzyme Inhibitors pharmacology, Ganglia, Spinal cytology, Molecular Sequence Data, Nerve Tissue Proteins genetics, Neuregulin-1, Neurons cytology, Neurons metabolism, PC12 Cells, Phosphorylation drug effects, Protein Kinase C-delta antagonists & inhibitors, Protein Kinase C-delta genetics, RNA Interference, Rats, Serine metabolism, Tetradecanoylphorbol Acetate pharmacology, Transfection, Avian Proteins metabolism, Nerve Growth Factors pharmacology, Nerve Tissue Proteins metabolism, Neurons drug effects, Protein Kinase C-delta metabolism
- Abstract
Proper, graded communication between different cell types is essential for normal development and function. In the nervous system, heart, and for some cancer cells, part of this communication requires signaling by soluble and membrane-bound factors produced by the NRG1 gene. We have previously shown that glial-derived neurotrophic factors activate a rapid, localized release of soluble neuregulin from neuronal axons that can, in turn promote proper axoglial development (Esper, R. M., and Loeb, J. A. (2004) J. Neurosci. 24, 6218-6227). Here we elucidate the mechanism of this localized, regulated release by implicating the delta isoform of protein kinase C (PKC). Blocking the PKC delta isoform with either rottlerin, a selective antagonist, or small interference RNA blocks the regulated release of neuregulin from both transfected cells and primary neuronal cultures. PKC activation also leads to the rapid phosphorylation of the pro-NRG1 cytoplasmic tail on serine residues adjacent to the membrane-spanning segment, that, when mutated markedly reduce the rate of NRG1 activity release. These findings implicate this specific PKC isoform as an important factor for the cleavage and neurotrophin-regulated release of soluble NRG1 forms that have important effects in nervous system development and disease.
- Published
- 2009
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