Unknown

Dataset Information

0

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


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.

SUBMITTER: Cottrell GS 

PROVIDER: S-EPMC2755963 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC8497002 | biostudies-literature
| S-EPMC9311399 | biostudies-literature
| S-EPMC7108872 | biostudies-literature
| S-EPMC10907292 | biostudies-literature
| S-EPMC4038561 | biostudies-literature
| S-EPMC5348388 | biostudies-literature
| S-EPMC2650347 | biostudies-literature
| S-EPMC10586804 | biostudies-literature
| S-EPMC5364067 | biostudies-literature
| S-EPMC9126669 | biostudies-literature