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Volume 272, Number 51, Issue of December 19, 1997
pp. 32686-32695
(Received for publication, May 16, 1997, and in revised form, October 8, 1997)
From the Department of Medicine, Division of Endocrinology, Beth
Israel Deaconess Medical Center, Harvard Medical School,
Boston, Massachusetts 02215
Leptin receptors include a long form (OBRl) with
302 cytoplasmic residues that is presumed to mediate most or all of
leptins signaling, and several short forms, including one (OBRs) that has 34 cytoplasmic residues, is widely expressed, and is presumed not
to signal but to mediate transport or clearance of leptin. We studied
the abilities of these two receptor isoforms to mediate signaling in
transfected cells. In response to leptin, OBRl, but not OBRs, underwent
tyrosine phosphorylation that was enhanced by co-expression with JAK2.
In cells expressing receptors and JAK2, both OBRs and OBRl mediated
leptin-dependent tyrosine phosphorylation of JAK2, and this
was abolished with OBRs when the Box 1 motif was mutated. In cells
expressing receptors, JAK2 and IRS-1, leptin induced tyrosine
phosphorylation of IRS-1 through OBRs and OBRl. In COS cells expressing
hemagglutinin-ERK1 and receptors, leptin increased ERK1 kinase activity
through OBRl, with the magnitude increased by co-expression of JAK1 or
JAK2, and to a lesser degree through OBRs, despite greater receptor
expression. In stable Chinese hamster ovary cell lines expressing OBRs
or OBRl, leptin stimulated endogenous ERK2 phosphorylation. Whereas
leptin stimulated tyrosine phosphorylation of hemagglutinin-STAT3 and
induction of a c-fos luciferase reporter plasmid through
OBRl, OBRs was without effect in these assays. In conclusion, OBRl is
capable of signaling to IRS-1 and mitogen-activated protein kinase via
JAK, in addition to activating STAT pathways. Although substantially
weaker than OBRl, OBRs is capable of mediating signal transduction via
JAK, but these activities are of as yet unknown significance for leptin biology in vivo.
Divergent Signaling Capacities of the Long and Short Isoforms
of the Leptin Receptor
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