TY - JOUR
T1 - Functional significance of type 1 insulin-like growth factor-mediated nuclear translocation of the insulin receptor substrate-1 and β-catenin
AU - Chen, Jia
AU - Wu, An
AU - Sun, Hongzhi
AU - Drakas, Robert
AU - Garofalo, Cecilia
AU - Cascio, Sandra
AU - Surmacz, Eva
AU - Baserga, Renato
PY - 2005/8/19
Y1 - 2005/8/19
N2 - Previous work has shown that the transcriptional regulator β-catenin can translocate to the nuclei when cells are stimulated with the type 1 insulin-like growth factor (IGF-1). We show by immunocoprecipitation and by confocal microscopy that β-catenin binds to and co-localizes with the insulin receptor substrate-1 (IRS-1), a docking protein for both the insulin and the IGF-1 receptors. IRS-1 is required for IGF-1-mediated nuclear translocation of β-catenin, resulting in the activation of the -catenin target genes. IGF-1-mediated nuclear translocation of β-catenin is facilitated by the nuclear translocation of IRS-1. Both IRS-1 and β-catenin are recruited to the cyclin D1 promoter, an established target for β-catenin, but only IRS-1 is recruited to the ribosomal DNA (rDNA) promoter. UBF proteins (known to interact with both IRS-1 and β-catenin) are also detectable in the cyclin D1 and rDNA promoters. These results indicate that IRS-1 (activated by the IGF-1 receptor) is one of several proteins that regulate the subcellular localization and activity of β-catenin. The ability of IRS-1 to localize to both RNA polymerase II (with β-catenin) and RNA polymerase I-regulated promoters suggest an explanation for the effect of IRS-1 on both cell growth in size and cell proliferation. This possibility is supported by the demonstration that enforced nuclear localization of IRS-1 causes nuclear translocation of β-catenin and transformation of normal mouse embryo fibroblasts (colony formation in soft agar).
AB - Previous work has shown that the transcriptional regulator β-catenin can translocate to the nuclei when cells are stimulated with the type 1 insulin-like growth factor (IGF-1). We show by immunocoprecipitation and by confocal microscopy that β-catenin binds to and co-localizes with the insulin receptor substrate-1 (IRS-1), a docking protein for both the insulin and the IGF-1 receptors. IRS-1 is required for IGF-1-mediated nuclear translocation of β-catenin, resulting in the activation of the -catenin target genes. IGF-1-mediated nuclear translocation of β-catenin is facilitated by the nuclear translocation of IRS-1. Both IRS-1 and β-catenin are recruited to the cyclin D1 promoter, an established target for β-catenin, but only IRS-1 is recruited to the ribosomal DNA (rDNA) promoter. UBF proteins (known to interact with both IRS-1 and β-catenin) are also detectable in the cyclin D1 and rDNA promoters. These results indicate that IRS-1 (activated by the IGF-1 receptor) is one of several proteins that regulate the subcellular localization and activity of β-catenin. The ability of IRS-1 to localize to both RNA polymerase II (with β-catenin) and RNA polymerase I-regulated promoters suggest an explanation for the effect of IRS-1 on both cell growth in size and cell proliferation. This possibility is supported by the demonstration that enforced nuclear localization of IRS-1 causes nuclear translocation of β-catenin and transformation of normal mouse embryo fibroblasts (colony formation in soft agar).
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U2 - 10.1074/jbc.M504516200
DO - 10.1074/jbc.M504516200
M3 - Article
C2 - 15967802
AN - SCOPUS:23844436626
VL - 280
SP - 29912
EP - 29920
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 33
ER -