EVIDENCE FOR AN INSULIN-RECEPTOR SUBSTRATE-1 INDEPENDENT INSULIN SIGNALING PATHWAY THAT MEDIATES INSULIN-RESPONSIVE GLUCOSE-TRANSPORTER (GLUT4) TRANSLOCATION

Interaction of the activated insulin receptor (IR) with its substrate, insulin receptor substrate 1 (IRS-1), via the phosphotyrosine binding domain of IRS-1 and the NPXY motif centered at phosphotyrosine 960 of the IR, is important for IRS-1 phosphorylation, We investigated the r ole of this interaction in the insulin signaling pathway that stimulat es glucose transport, Utilizing microinjection of competitive inhibito ry reagents in 3T3-L1 adipocytes, we have found that disruption of the IR/IRS-1 interaction has no effect upon translocation of the insulin- responsive glucose transporter (GLUT4). The activity of these reagents was demonstrated by their ability to block insulin stimulation of two distinct insulin bioeffects, membrane ruffling and mitogenesis, in 3T 3-L1 adipocytes and insulin-responsive rat 1 fibroblasts, These data s uggest that phosphorylated IRS-1 is not an essential component of the metabolic insulin signaling pathway that leads to GLUT4 translocation, yet it appears to be required for other insulin bioeffects.