Journal article
Constitutive Lysosomal Targeting and Degradation of Bovine Endothelin-converting Enzyme-1a Mediated by Novel Signals in Its Alternatively Spliced Cytoplasmic Tail
The Journal of biological chemistry, Vol.274(3), pp.1509-1518
01/1999
DOI: 10.1074/jbc.274.3.1509
PMID: 9880527
Abstract
Endothelin-converting enzyme-1 (ECE-1) is a type II membrane protein that catalyzes the proteolytic activation of big endothelin-1 to endothelin-1 (ET-1). The subcellular distribution of ECE-1, and hence the exact site of physiological activation of big ET-1, remains controversial. Here, we demonstrate with several complementary methods that the two alternatively spliced bovine ECE-1 isoforms, ECE-1a and ECE-1b, differing only in the first 30 amino acids of their N-terminal cytoplasmic tails, exhibit strikingly distinct intracellular sorting patterns. Bovine ECE-1a, which is responsible for the intracellular cleavage of big ET-1 in endothelial cells, is constitutively recruited into the lysosome, where it is rapidly degraded. In contrast, bovine ECE-1b, the isoform found in cultured smooth muscle cells, is transported to the plasma membrane by a default pathway and functions as an ectoenzyme. Mutational analyses reveal that the N-terminal tip of the cytoplasmic domain of bovine ECE-1a contains novel proline-containing signals that mediate constitutive lysosomal targeting. Analyses of chimeric ECE-1/transferrin receptors demonstrate that the cytoplasmic tail of bovine ECE-1a is sufficient for the lysosomal delivery and rapid degradation. Our results suggest that the distinct intracellular targeting of bovine ECE-1 isoforms may provide new insights into functional aspect of the endothelin system and that the cell permeability of ECE inhibitor compounds should be carefully considered during their pharmacological development.
Details
- Title: Subtitle
- Constitutive Lysosomal Targeting and Degradation of Bovine Endothelin-converting Enzyme-1a Mediated by Novel Signals in Its Alternatively Spliced Cytoplasmic Tail
- Creators
- Noriaki EmotoYudha NurhantariHaryanto AlimsardjonoJian XieTakahisa YamadaMasashi YanagisawaMasafumi Matsuo
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.274(3), pp.1509-1518
- DOI
- 10.1074/jbc.274.3.1509
- PMID
- 9880527
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Language
- English
- Date published
- 01/1999
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984094707802771
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