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Vol. 11, Issue 6, 1959-1972, June 2000
Division of Endocrinology and Department of Developmental and
Molecular Biology, Albert Einstein College of Medicine, Bronx, New York
10461
Recently, two different prohormone-processing enzymes, prohormone
convertase 1 (PC1) and carboxypeptidase E, have been implicated in
enhancing the storage of peptide hormones in endocrine secretory granules. It is important to know the extent to which such molecules may act as "sorting receptors" to allow the selective trafficking of cargo proteins from the trans-Golgi network into
forming granules, versus acting as enzymes that may indirectly
facilitate intraluminal storage of processed hormones within maturing
granules. GH4C1 cells primarily store prolactin in granules; they lack
PC1 and are defective for intragranular storage of transfected
proinsulin. However, proinsulin readily enters the immature granules of
these cells. Interestingly, GH4C1 clones that stably express modest levels of PC1 store more proinsulin-derived protein in granules. Even
in the presence of PC1, a sizable portion of the proinsulin that enters
granules goes unprocessed, and this portion largely escapes granule
storage. Indeed, all of the increased granule storage can be accounted
for by the modest portion converted to insulin. These results are not
unique to GH4C1 cells; similar results are obtained upon PC1 expression
in PC12 cells as well as in AtT20 cells (in which PC1 is expressed
endogenously at higher levels). An in vitro assay of protein solubility
indicates a difference in the biophysical behavior of proinsulin and
insulin in the PC1 transfectants. We conclude that processing to
insulin, facilitated by the catalytic activities of granule proteolytic
enzymes, assists in the targeting (storage) of the hormone.
Corresponding author. E-mail address:
arvan{at}aecom.yu.edu.
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