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 P13-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.