Endothelin-converting enzyme-1 regulates endosomal sorting of calcitonin receptor-like receptor and beta-arrestins.
Although cell surface metalloendopeptidases degrade neuropeptides in the extracellular fluid to terminate signaling, the function of peptidases in endosomes is unclear. We report that isoforms of endothelin-converting enzyme-1 (ECE-1a-d) are present in early endosomes, where they degrade neuropeptides and regulate post-endocytic sorting of receptors. Calcitonin gene-related peptide (CGRP) co-internalizes with ... calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), beta-arrestin2, and ECE-1 to early endosomes, where ECE-1 degrades CGRP. CGRP degradation promotes CLR/RAMP1 recycling and beta-arrestin2 redistribution to the cytosol. ECE-1 inhibition or knockdown traps CLR/RAMP1 and beta-arrestin2 in endosomes and inhibits CLR/RAMP1 recycling and resensitization, whereas ECE-1 overexpression has the opposite effect. ECE-1 does not regulate either the resensitization of receptors for peptides that are not ECE-1 substrates (e.g., angiotensin II), or the recycling of the bradykinin B(2) receptor, which transiently interacts with beta-arrestins. We propose a mechanism by which endosomal ECE-1 degrades neuropeptides in endosomes to disrupt the peptide/receptor/beta-arrestin complex, freeing internalized receptors from beta-arrestins and promoting recycling and resensitization.
Mesh Terms:
Angiotensin I, Angiotensin II, Animals, Arrestins, Aspartic Acid Endopeptidases, Bradykinin, Calcitonin Gene-Related Peptide, Calcitonin Receptor-Like Protein, Cell Line, Tumor, Cell Membrane, Endocytosis, Endosomes, Enzyme Inhibitors, Humans, Hydrogen-Ion Concentration, Hydrolysis, Intracellular Signaling Peptides and Proteins, Isoenzymes, Membrane Proteins, Metalloendopeptidases, Protein Binding, Protein Transport, Rats, Receptor Activity-Modifying Protein 1, Receptor Activity-Modifying Proteins, Receptor, Angiotensin, Type 1, Receptors, Calcitonin, Signal Transduction
Angiotensin I, Angiotensin II, Animals, Arrestins, Aspartic Acid Endopeptidases, Bradykinin, Calcitonin Gene-Related Peptide, Calcitonin Receptor-Like Protein, Cell Line, Tumor, Cell Membrane, Endocytosis, Endosomes, Enzyme Inhibitors, Humans, Hydrogen-Ion Concentration, Hydrolysis, Intracellular Signaling Peptides and Proteins, Isoenzymes, Membrane Proteins, Metalloendopeptidases, Protein Binding, Protein Transport, Rats, Receptor Activity-Modifying Protein 1, Receptor Activity-Modifying Proteins, Receptor, Angiotensin, Type 1, Receptors, Calcitonin, Signal Transduction
J. Cell Biol.
Date: Dec. 03, 2007
PubMed ID: 18039931
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