Functional significance of type 1 insulin-like growth factor-mediated nuclear translocation of the insulin receptor substrate-1 and beta-catenin.
Previous work has shown that the transcriptional regulator beta-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 beta-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 beta-catenin, resulting in the activation of the beta-catenin target genes. IGF-1-mediated nuclear translocation of beta-catenin is facilitated by the nuclear translocation of IRS-1. Both IRS-1 and beta-catenin are recruited to the cyclin D1 promoter, an established target for beta-catenin, but only IRS-1 is recruited to the ribosomal DNA (rDNA) promoter. UBF proteins (known to interact with both IRS-1 and beta-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 beta-catenin. The ability of IRS-1 to localize to both RNA polymerase II (with beta-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 beta-catenin and transformation of normal mouse embryo fibroblasts (colony formation in soft agar).
Chen
Jia
J
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Wu
An
A
Sun
Hongzhi
H
Drakas
Robert
R
Garofalo
Cecilia
C
Cascio
Sandra
S
Surmacz
Eva
E
Baserga
Renato
R
D016475:3T3 Cells; D021581:Active Transport, Cell Nucleus; D000818:Animals; D019938:Cyclin D1 / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004275:DNA, Ribosomal / Q000235:genetics; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D051379:Mice; D018613:Microscopy, Confocal; D010750:Phosphoproteins / Q000378:metabolism*; D035463:Pol1 Transcription Initiation Complex Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000378:metabolism*; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004275:DNA, Ribosomal; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D035463:Pol1 Transcription Initiation Complex Proteins; D015534:Trans-Activators; D051176:beta Catenin; C063844:transcription factor UBF; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I