Functional Significance of Type 1 Insulin-like Growth Factor-mediated Nuclear Translocation of the Insulin Receptor Substrate-1 and β-Catenin

• Published in: The Journal of biological chemistry Vol. 280; no. 33; p. 29912
• Main Authors: Jia Chen, An Wu, Hongzhi Sun, Robert Drakas, Cecilia Garofalo, Sandra Cascio, Eva Surmacz, Renato Baserga
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 19.08.2005
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M504516200

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 β-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).