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J Biol Chem, Vol. 273, Issue 29, 18365-18373, July 17, 1998
From the Leptin and the leptin receptor are key players in
the regulation of body weight. In an attempt to dissect the molecular
mechanism of the Zucker fatty rat leptin receptor mutation
(Gln269
Altered Cell Surface Expression and Signaling of Leptin
Receptors Containing the fatty Mutation
,
,
Department of Biochemistry and Molecular
Biology, University of Southern California, Los Angeles, California
90033 and the Departments of § Cell Biology,
¶ Mammalian Cell Molecular Biology, Molecular Genomics,
** Neuroscience, and Computational Biology,
Amgen Inc., Thousand Oaks, California 91320
Pro) we analyzed the effects of this mutation
on leptin receptor signaling and expression in three different
expression systems: 1) 32D cells expressing leptin/erythropoietin
receptor chimeras, 2) COS-7 cells expressing a leptin receptor short
form, and 3) 293 cells expressing soluble receptor forms. To determine
if the Gln269 Pro mutation is critical for the observed
phenotype, we made a similar Gln Pro mutation at a vicinal residue
two amino acids upstream of the fatty mutation to see if it
would have similar effects. Incorporation of either of the Gln Pro
mutations into wild type receptor forms did not interfere with leptin
binding, but it resulted in a signaling-incompetent receptor. In
addition, the majority of the mutant receptor protein was localized
intracellularly. Our results suggest that the obese phenotype resulting
from the Gln269 Pro mutation in the leptin receptor of
the Zucker fatty rat may be due not only to a reduced cell
surface expression of this form of the leptin receptor, but also to a
post-leptin binding malfunction of the receptor that interferes with
subsequent signal transduction.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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