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

Research output: Contribution to journalArticle

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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Arrestin
Endothelins
Arrestins
Substance P
Endosomes
Enzymes
G-Protein-Coupled Receptors
Cell death
Mitogen-Activated Protein Kinases
Cell Death
Metalloendopeptidases
Chemical activation
Neurokinin-1 Receptors
Death Domain Receptors
Phosphorylation
Extracellular Fluid
Cytoplasmic and Nuclear Receptors
Endocytosis
Neuropeptides
Cytosol

Cite this

Cottrell, G. S., Padilla, B. E., Amadesi, S., Poole, D. P., Murphy, J. E., Hardt, 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

Endosomal Endothelin-converting Enzyme-1: A Regulator of β-Arrestin-Dependent ERK Signaling. / Cottrell, Graeme S; Padilla, B E; Amadesi, S; Poole, D P; Murphy, J E; Hardt, M; Roosterman, D; Steinhoff, M; Bunnett, N W.

In: Journal of Biological Chemistry, Vol. 284, No. 33, 14.08.2009, p. 22411-22425.

Research output: Contribution to journalArticle

Cottrell, GS, Padilla, BE, Amadesi, S, Poole, DP, Murphy, JE, Hardt, M, Roosterman, D, Steinhoff, M & Bunnett, NW 2009, 'Endosomal Endothelin-converting Enzyme-1: A Regulator of β-Arrestin-Dependent ERK Signaling', Journal of Biological Chemistry, vol. 284, no. 33, pp. 22411-22425. https://doi.org/10.1074/jbc.M109.026674
Cottrell GS, Padilla BE, Amadesi S, Poole DP, Murphy JE, Hardt M et al. Endosomal Endothelin-converting Enzyme-1: A Regulator of β-Arrestin-Dependent ERK Signaling. Journal of Biological Chemistry. 2009 Aug 14;284(33):22411-22425. https://doi.org/10.1074/jbc.M109.026674
Cottrell, Graeme S ; Padilla, B E ; Amadesi, S ; Poole, D P ; Murphy, J E ; Hardt, M ; Roosterman, D ; Steinhoff, M ; Bunnett, N W. / Endosomal Endothelin-converting Enzyme-1: A Regulator of β-Arrestin-Dependent ERK Signaling. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 33. pp. 22411-22425.
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