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J. Biol. Chem., Vol. 275, Issue 21, 15985-15991, May 26, 2000
From the INSERM U145, IFR-50, Faculté de Médecine,
06107 Nice Cédex 2, France and The SOCS proteins are induced by several
cytokines and are involved in negative feedback loops. Here we
demonstrate that in 3T3-L1 adipocytes, insulin, a hormone whose
receptor does not belong to the cytokine receptor family, induces
SOCS-3 expression but not CIS or SOCS-2. Using transfection of COS-7
cells, we show that insulin induction of SOCS-3 is enhanced upon Stat5B
expression. Moreover, Stat5B from insulin-stimulated cells binds
directly to a Stat element present in the SOCS-3 promoter. Once
induced, SOCS-3 inhibits insulin activation of Stat5B without modifying the insulin receptor tyrosine kinase activity. Two pieces of evidence suggest that this negative regulation likely results from competition between SOCS-3 and Stat5B binding to the same insulin receptor motif.
First, using a yeast two-hybrid system, we show that SOCS-3 binds to
the insulin receptor at phosphotyrosine 960, which is precisely where
Stat5B binds. Second, using confocal microscopy, we show that insulin
induces translocation of SOCS-3 from an intracellular compartment to
the cell membrane, leading to colocalization of SOCS-3 with the insulin
receptor. This colocalization is dependent upon phosphorylation of
insulin receptor tyrosine 960. Indeed, in cells expressing an insulin
receptor mutant in which tyrosine 960 has been mutated to
phenylalanine, insulin does not modify the cellular localization of
SOCS-3. We have thus revealed an insulin target gene of which the
expression is potentiated upon Stat5B activation. By inhibiting
insulin-stimulated Stat5B, SOCS-3 appears to function as a negative
regulator of insulin signaling.
SOCS-3 Is an Insulin-induced Negative Regulator of Insulin
Signaling*
,§,
, and The Walter and Eliza Hall
Institute for Medical Research and The Cooperative Research Center for
Cellular Growth Factor, Parkville, Victoria 3050, Australia
*
This work was supported by the INSERM, the Université
de Nice-Sophia Antipolis, Groupe LIPHA-Merck (Lyon, France),
Association pour la Recherche contre le Cancer Grant 9330, and La
Fondation de France Grant 9800228.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.
Both authors contributed equally to this work.
§
To whom correspondence should be addressed: INSERM U145, IFR-50,
Faculté de Médecine, 06107 Nice Cédex 2, France.
Tel.: 33 4 93 81 54 47; Fax: 33 4 93 81 54 32; E-mail:
peraldi@unice.fr.
¶
A recipient of a Naturalia Biologica fellowship.
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