The role of insulin receptor substrate-1 in transformation by v-src.
The insulin receptor substrate-1 (IRS-1), a docking protein for both the insulin (InR) and the insulin-like growth factor-1 (IGF-IR) receptors, sends a mitogenic, anti-differentiation and transforming signal. We now show that down-regulation of IRS-1 in cells transformed by v-src reverses the transformed phenotype (growth in serum-free medium and colony formation in soft agar). IRS-1 translocates to nuclei and is found in the cyclin D1 and rDNA promoters. Stat3, which is activated by src, requires both IRS-1 and src for promoter occupancy. IRS-1 (by itself or in combination with src) also markedly increases transcription from these two promoters. We also show that IRS-1 binds to src via its two PI3-K binding tyrosine residues, and that these two residues are required for transformation of mammary cancer cells expressing v-src. Taken together, these results indicate a significant role of IRS-1 in the activation of cell cycle progression genes and transformation of cells by v-src.
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Hongzhi
H
Sun
Renato
R
Baserga
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics; D004275:DNA, Ribosomal / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D018613:Microscopy, Confocal; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D004275:DNA, Ribosomal; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D035683:MicroRNAs; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D015688:Oncogene Protein pp60(v-src); D016392:Proto-Oncogene Proteins pp60(c-src)