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

J Biol Chem. 2009 Aug 14;284(33):22411-25. doi: 10.1074/jbc.M109.026674. Epub 2009 Jun 16.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrestins / metabolism*
  • Aspartic Acid Endopeptidases / chemistry*
  • Aspartic Acid Endopeptidases / physiology*
  • Cell Nucleus / metabolism
  • Cytosol / metabolism
  • DNA-Binding Proteins / metabolism
  • Endosomes / metabolism*
  • Endothelin-Converting Enzymes
  • Humans
  • MAP Kinase Signaling System
  • Male
  • Metalloendopeptidases / chemistry*
  • Metalloendopeptidases / 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
  • beta-Arrestins

Substances

  • Arrestins
  • DNA-Binding Proteins
  • NR4A1 protein, human
  • Nr4a1 protein, mouse
  • Nr4a1 protein, rat
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Receptors, Steroid
  • beta-Arrestins
  • Mitogen-Activated Protein Kinase 1
  • Aspartic Acid Endopeptidases
  • Metalloendopeptidases
  • ECE1 protein, human
  • Ece1 protein, mouse
  • Endothelin-Converting Enzymes