Endosomal endothelin-converting enzyme-1: A regulator of beta-arrestin-dependent ERK signaling

Graeme Cottrell, Benjamin Padilla, Silvia Amadesi, Daniel Poole, Jane Murphy, Markus Hardt, Dirk Roosterman, Martin Steinhoff, Nigel Bunnett

Research output: Contribution to journalArticleResearchpeer-review

50 Citations (Scopus)

Abstract

Neuropeptide signaling at the cell surface is regulated by metalloendopeptidases, which degrade peptides in the extracellular fluid, and beta-arrestins, which interact with G protein-coupled receptors (GPCRs) to mediate desensitization. beta-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, beta-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 beta-arrestin-dependent signaling of endocytosed GPCRs.
Original languageEnglish
Pages (from-to)22411 - 22425
Number of pages15
JournalThe Journal of Biological Chemistry
Volume284
Issue number33
DOIs
Publication statusPublished - 2009

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