Accessibility navigation

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

Cottrell, G. ORCID:, 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

Full text not archived in this repository.

It is advisable to refer to the publisher's version if you intend to cite from this work. See Guidance on citing.

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


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
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

University Staff: Request a correction | Centaur Editors: Update this record

Page navigation