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J Biol Chem, Vol. 275, Issue 19, 14563-14572, May 12, 2000
From the The adipocyte-derived hormone leptin signals the
status of body energy stores by activating the long form of the leptin
receptor (LRb). Activation of LRb results in the activation of the
associated Jak2 tyrosine kinase and the transmission of downstream
phosphotyrosine-dependent signals. We have investigated the
signaling function of mutant LRb intracellular domains under the
control of the extracellular erythropoietin (Epo) receptor. By using
this system, we confirm that two tyrosine residues in the intracellular
domain of murine LRb become phosphorylated to mediate LRb signaling;
Tyr985 controls the tyrosine phosphorylation of
SHP-2, and Tyr1138 controls STAT3 activation. We
furthermore investigated the mechanisms by which LRb controls
downstream ERK activation and c-fos and SOCS3 message
accumulation. Tyr985-mediated recruitment of SHP-2 does not
alter tyrosine phosphorylation of Jak2 or STAT3 but results in GRB-2
binding to tyrosine-phosphorylated SHP-2 and is required for the
majority of ERK activation during LRb signaling. Tyr985 and
ERK activation similarly mediate c-fos mRNA
accumulation. In contrast, SOCS3 mRNA accumulation requires
Tyr1138-mediated STAT3 activation. Thus, the two LRb
tyrosine residues that are phosphorylated during receptor activation
mediate distinct signaling pathways as follows: SHP-2 binding to
Tyr985 positively regulates the ERK
Activation of Downstream Signals by the Long Form of the
Leptin Receptor*
§¶,§,, and
Research Division, Joslin Diabetes Center
and Department of Medicine, Harvard Medical School,
Boston, Massachusetts 02215
c-fos
pathway, and STAT3 binding to Tyr1138 mediates the
inhibitory SOCS3 pathway.
*
This work was supported by National Institutes of Health
Grant DK 56731 and a new investigator grant from The Medical
Foundation/Harcourt General Charitable Trust (to M. G. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The 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:
Research Division, Joslin Diabetes Center, 1 Joslin Place, Boston, MA
02130. Tel.: 617-735-1967; Fax: 617-735-1970; E-mail:
martin.myers@joslin.harvard.edu.
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