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Originally published In Press as doi:10.1074/jbc.M305690200 on June 7, 2003
J. Biol. Chem., Vol. 278, Issue 34, 31486-31494, August 22, 2003
The Trafficking of 1-Antitrypsin, a Post-Golgi Secretory Pathway Marker, in INS-1 Pancreatic Beta Cells*
Lijun Feng and
Peter Arvan
From the
Division of Endocrinology and Department of Developmental and Molecular
Biology, Albert Einstein College of Medicine, Bronx, New York 10461
A sulfated 1-antitrypsin (AAT), thought to be a default
secretory pathway marker, is not stored in secretory granules when expressed
in neuroendocrine PC12 cells. In search of a constitutive secretory pathway
marker for pancreatic beta cells, we produced INS-1 cells stably expressing
wild-type AAT. Because newly synthesized AAT arrives very rapidly in the Golgi
complex, kinetics alone cannot resolve AAT release via distinct secretory
pathways, although most AAT is secreted within a few hours and virtually none
is stored in mature granules. Nevertheless, from pulse-chase analyses, a major
fraction of newly synthesized AAT transiently exhibits secretogogue-stimulated
exocytosis and localizes within immature secretory granules (ISGs). This
trafficking occurs without detectable AAT polymerization or binding to lipid
rafts. Remarkably, in a manner not requiring its glycans, all of the newly
synthesized AAT is then removed from granules during their maturation, leading
mostly to constitutive-like AAT secretion, whereas a smaller fraction
( 10%) goes on to lysosomes. Secretogogue-stimulated ISG exocytosis
reroutes newly synthesized AAT directly into the medium and prevents its
arrival in lysosomes. These data are most consistent with the idea that
soluble AAT abundantly enters ISGs and then is efficiently relocated to the
endosomal system, from which many molecules undergo constitutive-like
secretion while a smaller fraction advances to lysosomes.
Received for publication, May 30, 2003
* This work was supported by National Institutes of Health Grant DK48280, an
American Diabetes Association mentor-based postdoctoral award, and a grant
from the AlphaOne Foundation (all to P. A.). The costs of publication of this
article were defrayed in part by the payment of page charges. This article
must therefore be hereby marked "advertisement" in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: Division of Endocrinology,
University of Michigan, MSRB2 Rm. 5560, 1500 W. Medical Center Dr., Ann Arbor,
MI 48109. Tel.: 734-936-5505; Fax: 734-651-4499; E-mail:
parvan{at}umich.edu.

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Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.
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