Neurotrophins induce neuregulin release through protein kinase Cdelta activation.
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.
Esper
Raymond M
RM
Department of Neurology, Wayne State University, Detroit, Michigan 48201, USA.
Loeb
Jeffrey A
JA
D000098:Acetophenones / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D030161:Avian Proteins / Q000235:genetics / Q000378:metabolism*; D001578:Benzopyrans / Q000494:pharmacology; D015153:Blotting, Western; D016466:CHO Cells; D002478:Cells, Cultured; D002642:Chick Embryo; D002645:Chickens; D006224:Cricetinae; D003412:Cricetulus; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020890:Neuregulin-1; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D012694:Serine / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
D000098:Acetophenones; D030161:Avian Proteins; D001578:Benzopyrans; D004791:Enzyme Inhibitors; C490582:NRG1 protein, Gallus gallus; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D012694:Serine; C085746:rottlerin; D051745:Protein Kinase C-delta; D013755:Tetradecanoylphorbol Acetate