Insulin-like growth factor I receptor signaling and nuclear translocation of insulin receptor substrates 1 and 2.

The insulin receptor substrate 1 (IRS-1) can translocate to the nuclei and nucleoli of several types of cells. Nuclear translocation can be induced by an activated insulin-like growth factor 1 receptor (IGF-IR), and by certain oncogenes, such as the Simian virus 40 T antigen and v-src. We have asked whether ...
IRS-2 could also translocate to the nuclei. In addition, we have studied the effects of functional mutations in the IGF-IR on nuclear translocation of IRS proteins. IRS-2 translocates to the nuclei of mouse embryo fibroblasts expressing the IGF-IR, but, at variance with IRS-1, does not translocate in cells expressing the Simian virus 40 T antigen. Mutations in the tyrosine kinase domain of the IGF-IR abrogate translocation of the IRS proteins. Other mutations in the IGF-IR, which do not interfere with its mitogenicity but inhibit its transforming capacity, result in a decrease in translocation, especially to the nucleoli. Nuclear IRS-1 and IRS-2 interact with the upstream binding factor, which is a key regulator of RNA polymerase I activity and, therefore, rRNA synthesis. In 32D cells, wild-type, but not mutant, IRS-1 causes a significant activation of the ribosomal DNA promoter. The interaction of nuclear IRS proteins with upstream binding factor 1 constitutes the first direct link of these proteins with the ribosomal DNA transcription machinery.
Mesh Terms:
3T3 Cells, Active Transport, Cell Nucleus, Animals, Blotting, Western, Cell Nucleus, Immunohistochemistry, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins, Mice, Microscopy, Confocal, Mutation, Phosphoproteins, Phosphorylation, Pol1 Transcription Initiation Complex Proteins, RNA, Ribosomal, Receptor, IGF Type 1, Signal Transduction, Subcellular Fractions
Mol. Endocrinol.
Date: Mar. 01, 2003
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