Nuclear IRS-3 Can Transactivate Genes

Science's STKE  05 Mar 2002:
Vol. 2002, Issue 122, pp. tw96
DOI: 10.1126/stke.2002.122.tw96

The members of the insulin receptor substrate (IRS) family are docking proteins that participate in transducing signals that emanate from several different receptors. Kabuta et al. studied IRS-3 and found that it localized to the nucleus and might transactivate gene expression. Overexpression of IRS-1, IRS-2, or IRS-4 in cells resulted in the localization of these proteins in the cytoplasm or at the plasma membrane, whereas IRS-3 localized to the plasma membrane and nucleus. Deletion analysis of IRS-3 revealed that a region not well conserved in the other IRS proteins was essential for nuclear targeting. These data indicate that IRS-3 may be the only IRS protein that can shuttle to the nucleus. But what is its function there? Human embryonic kidney (HEK) 293 cells were transfected with a Gal4 promoter-driving gene reporter and chimeras of the Gal4 DNA-binding domain fused to segments of IRS-3. Although neither the full-length IRS-3 nor an NH2-terminal portion of IRS-3 could drive expression from the gene reporter, a 200-amino acid COOH-terminal fragment of IRS-3 stimulated gene expression from the reporter plasmid. These data suggest that IRS-3 might not only function as a docking protein for signaling proteins in the cytoplasm, but that IRS-3 might also participate in activating gene expression.

T. Kabuta, F. Hakuno, T. Asano, S.-I. Takahashi, Insulin receptor substrate-3 functions as transcriptional activator in the nucleus. J. Biol. Chem. 277, 6846-6851 (2002). [Abstract] [Full Text]