Endosomal Endothelin-converting Enzyme-1: A Regulator of β-Arrestin-Dependent ERK Signaling

Graeme S Cottrell, B E Padilla, S Amadesi, D P Poole, J E Murphy, M Hardt, D Roosterman, M Steinhoff, N W Bunnett

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49 Citations (Scopus)

Abstract

Neuropeptide signaling at the cell surface is regulated by metalloendopeptidases, which degrade peptides in the extracellular fluid, and β-arrestins, which interact with G protein-coupled receptors (GPCRs) to mediate desensitization. β-Arrestins also recruit GPCRs and mitogen-activated protein kinases to endosomes to allow internalized receptors to continue signaling, but the mechanisms regulating endosomal signaling are unknown. We report that endothelin-converting enzyme-1 (ECE-1) degrades substance P (SP) in early endosomes of epithelial cells and neurons to destabilize the endosomal mitogen-activated protein kinase signalosome and terminate signaling. ECE-1 inhibition caused endosomal retention of the SP neurokinin 1 receptor, β-arrestins, and Src, resulting in markedly sustained ERK2 activation in the cytosol and nucleus, whereas ECE-1 overexpression attenuated ERK2 activation. ECE-1 inhibition also enhanced SP-induced expression and phosphorylation of the nuclear death receptor Nur77, resulting in cell death. Thus, endosomal ECE-1 attenuates ERK2-mediated SP signaling in the nucleus to prevent cell death. We propose that agonist availability in endosomes, here regulated by ECE-1, controls β-arrestin-dependent signaling of endocytosed GPCRs.
Original languageEnglish
Pages (from-to)22411-22425
Number of pages15
JournalJournal of Biological Chemistry
Volume284
Issue number33
DOIs
Publication statusPublished - 14 Aug 2009

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    Cottrell, G. S., Padilla, B. E., Amadesi, S., Poole, D. P., Murphy, J. E., Hardt, M., Roosterman, D., Steinhoff, M., & Bunnett, N. W. (2009). Endosomal Endothelin-converting Enzyme-1: A Regulator of β-Arrestin-Dependent ERK Signaling. Journal of Biological Chemistry, 284(33), 22411-22425. https://doi.org/10.1074/jbc.M109.026674