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

Cottrell, G., Padilla, B. E., Amadesi, S., Poole, D. P., Murphy, J. E., Hardt, M., Roosterman, D., Steinhoff, M. and Bunnett, N. W. (2009) Endosomal endothelin-converting enzyme-1: a regulator of beta-arrestin-dependent ERK signaling. Journal of Biological Chemistry, 284 (33). pp. 22411-22425. ISSN 1083-351X

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To link to this item DOI: 10.1074/jbc.M109.026674

Abstract/Summary

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.

Item Type:Article
Refereed:Yes
Divisions:No Reading authors. Back catalogue items
ID Code:30258
Uncontrolled Keywords:Animals Arrestins/*metabolism Aspartic Acid Endopeptidases/*chemistry/*physiology Cell Nucleus/metabolism Cytosol/metabolism DNA-Binding Proteins/metabolism Endosomes/*metabolism Humans MAP Kinase Signaling System Male Metalloendopeptidases/*chemistry/*physiology Mice Mice, Inbred C57BL Mitogen-Activated Protein Kinase 1/*metabolism Models, Biological Nuclear Receptor Subfamily 4, Group A, Member 1 Rats Rats, Sprague-Dawley Receptors, Steroid/metabolism Signal Transduction
Additional Information:Full text freely available via PubMed Cottrell, Graeme S Padilla, Benjamin E Amadesi, Silvia Poole, Daniel P Murphy, Jane E Hardt, Markus Roosterman, Dirk Steinhoff, Martin Bunnett, Nigel W DK39957/DK/NIDDK NIH HHS/ DK43207/DK/NIDDK NIH HHS/ FS/08/017/25027/British Heart Foundation/United Kingdom J Biol Chem. 2009 Aug 14;284(33):22411-25. Epub 2009 Jun 16.
Publisher:American Society for Biochemistry and Molecular Biology

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