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J Biol Chem, Vol. 274, Issue 21, 15262-15270, May 21, 1999
From the Insulin receptor substrates (IRS) mediate
biological actions of insulin, growth factors, and cytokines. All four
mammalian IRS proteins contain pleckstrin homology (PH) and
phosphotyrosine binding (PTB) domains at their N termini. However, the
molecules diverge in their C-terminal sequences. IRS3 is considerably
shorter than IRS1, IRS2, and IRS4, and is predicted to interact with a distinct group of downstream signaling molecules. In the present study,
we investigated interactions of IRS3 with various signaling molecules.
The PTB domain of mIRS3 is necessary and sufficient for binding to the
juxtamembrane NPXpY motif of the insulin receptor in the
yeast two-hybrid system. This interaction is stronger if the PH domain
or the C-terminal phosphorylation domain is retained in the construct.
As determined in a modified yeast two-hybrid system, mIRS3 bound
strongly to the p85 subunit of phosphatidylinositol 3-kinase. Although
high affinity interaction required the presence of at least two of the
four YXXM motifs in mIRS3, there was not a requirement for
specific YXXM motifs. mIRS3 also bound to SHP2, Grb2, Nck,
and Shc, but less strongly than to p85. Studies in COS-7 cells
demonstrated that deletion of either the PH or the PTB domain abolished
insulin-stimulated phosphorylation of mIRS3. Insulin stimulation
promoted the association of mIRS3 with p85, SHP2, Nck, and Shc. Despite
weak association between mIRS3 and Grb2, this interaction was not
increased by insulin, and may not be mediated by the SH2 domain of
Grb2. Thus, in contrast to other IRS proteins, mIRS3 appears to have
greater specificity for activation of the phosphatidylinositol 3-kinase
pathway rather than the Grb2/Ras pathway.
Interaction of Insulin Receptor Substrate 3 with Insulin
Receptor, Insulin Receptor-related Receptor, Insulin-like Growth
Factor-1 Receptor, and Downstream Signaling Proteins
,§, and
Diabetes Branch, NIDDK, National Institutes
of Health, Bethesda, Maryland 20892 and the § Graduate
Genetics Program, George Washington University,
Washington, D. C. 20052
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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