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J Biol Chem, Vol. 273, Issue 39, 25339-25346, September 25, 1998
From the Institut de Pharmacologie Moléculaire et Cellulaire
du CNRS, Université de Nice-Sophia Antipolis, Sophia Antipolis,
660 Route des Lucioles, 06560 Valbonne, France, the
¶ Montreal Neurological Institute, McGill University,
Montréal, Québec H3A 2B4, Canada, and the
§ Laboratory of Biochemical Neuroendocrinology, Clinical
Research Institute of Montréal,
Montréal, Québec H2W 1R7, Canada
Among the members of the proprotein convertase
(PC) family, PC1 and PC2 have well established roles as prohormone
convertases. Another good candidate for this role is PC5-A that has
been shown to be present in the regulated secretory pathway of certain
neuroendocrine tissues, but evidence that it can process prohormones is
lacking. To determine whether PC5-A could function as a prohormone
convertase and to compare its cleavage specificity with that of PC1 and
PC2, we stably transfected the rat pheochromocytoma PC12 cell line with
PC5-A and analyzed the biosynthesis and subcellular localization of the
enzyme, as well as its ability to process pro-neurotensin/neuromedin N
(pro-NT/NN) into active peptides. Our data showed that in transfected PC12 cells, PC5-A was converted from its 126-kDa precursor form into a
117-kDa mature form and, to a lesser extent, into a C-terminally truncated 65-kDa form of the 117-kDa product. Metabolic and
immunochemical studies showed that PC5-A was sorted to early
compartments of the regulated secretory pathway where it colocalized
with immunoreactive NT. Furthermore, pro-NT/NN was processed in these
compartments according to a pattern that differed from that previously
described in PC1- and PC2-transfected PC12 cells. This pattern
resembled that previously reported for pro-NT/NN processing in the
adrenal medulla, a tissue known to express high levels of PC5-A.
Altogether, these data demonstrate for the first time the ability of
PC5-A to function as a prohormone convertase in the regulated secretory pathway and suggest a role for this enzyme in the physiological processing of pro-NT/NN.
PC5-A-mediated Processing of Pro-neurotensin in Early
Compartments of the Regulated Secretory Pathway of PC5-transfected
PC12 Cells
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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