Endothelin-converting enzyme-1 regulates endosomal sorting of calcitonin receptor-like receptor and beta-arrestins
AuthorPadilla, BE; Cottrell, GS; Roosterman, D; Pikios, S; Muller, L; Steinhoff, M; Bunnett, NW
Source TitleThe Journal of Cell Biology
PublisherROCKEFELLER UNIV PRESS
University of Melbourne Author/sBunnett, Nigel
AffiliationPharmacology and Therapeutics
Document TypeJournal Article
CitationsPadilla, B. E., Cottrell, G. S., Roosterman, D., Pikios, S., Muller, L., Steinhoff, M. & Bunnett, N. W. (2007). Endothelin-converting enzyme-1 regulates endosomal sorting of calcitonin receptor-like receptor and beta-arrestins. JOURNAL OF CELL BIOLOGY, 179 (5), pp.981-997. https://doi.org/10.1083/jcb.200704053.
Access StatusOpen Access
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.
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