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J Biol Chem, Vol. 274, Issue 3, 1509-1518, January 15, 1999
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From the 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.
Division of Genetics, International Center
for Medical Research, Kobe University School of Medicine, Kobe, 6500017 Japan and the ¶ Howard Hughes Medical Institute and Department of
Molecular Genetics, University of Texas Southwestern Medical Center at
Dallas, Dallas, Texas 75235-9050
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