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J. Biol. Chem., Vol. 277, Issue 7, 4845-4852, February 15, 2002
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From Endocrinologie et Métabolisme, CNRS UPR 1524 Institut
Cochin de Genetique Moleculaire, 24 rue du Faubourg
Saint-Jacques, 75674 Paris Cedex 14, France
Grb14 belongs to the Grb7 family of adapters and
was recently identified as a partner of the insulin receptor (IR). Here
we show that Grb14 inhibits in vitro IR substrate
phosphorylation. Grb14 does not alter the Km for
ATP and behaves as an uncompetitive inhibitor for the IR substrate.
Similar experiments performed with other members of the Grb7 family,
Grb7 and Grb10, and with IGF-1 receptor argue in favor of a specific
inhibition of the IR catalytic activity by Grb14. The IR-interacting
domain of Grb14, the PIR, is sufficient for the inhibitory effect of Grb14, whereas the SH2 domain has no effect on IR catalytic activity. In Chinese hamster ovary (CHO) cells overexpressing both IR and Grb14,
Grb14 binds to the IR as early as 1 min after insulin stimulation, and
the two proteins remain associated. When interacting with Grb14, the IR
is protected against tyrosine phosphatases action and therefore
maintained under a phosphorylated state. However, the binding of Grb14
to the IR induces an early delay in the activation of Akt and ERK1/2 in
CHO-IR cells, and ERK1/2 are less efficiently phosphorylated. These
findings show that Grb14 is a direct inhibitor of the IR catalytic
activity and could be considered as a modulator of insulin signaling.
Inhibition of Insulin Receptor Catalytic Activity by the
Molecular Adapter Grb14*
,
*
This work was supported by Association pour la Recherche sur
le Cancer Grants 9111 and 5237 (to A.-F. B.) and by LIPHA S.A.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.
Recipient of a fellowship from the Ministère de la Recherche.
§
Current address: Dept. of Molecular Genetics, University of Texas,
Southwestern Medical Center, 5325 Harry Hines Blvd., Dallas, TX
75235-9046.
¶
To whom correspondence should be addressed. Tel.:
33-1-53-73-27-09; Fax: 33-1-53-73-27-03; E-mail:
burnol@cochin.inserm.fr.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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