GTP-binding protein-activator sequences in the insulin receptor

Some functions of the insulin receptor (insR) are assumed to be mediated by pertussis toxin-sensitive Gi/Go. proteins. Here we have located G-protein-activator domains in the cytoplasmic region of the human insR. We searched the sequence of insR and found three candidate regions at residues 1039-1061, 1147-1168 and 1325-1345, referred to as ISRP 1, ISRP2 and ISRP3, respectively. Among them, the Gi/Go-activating function was observed only in peptide ISRP3. ISRP1 specifically activated G3, whereas ISRP2 had no effect on G proteins. ISRP2 and ISRP3 contained five of six autophosphorylated tyrosine residues in insR. After tyrosine phosphorylation, ISRP2 showed specific G1-activating function, and ISRP3 potentiated its ability and became capable of activating G proteins generally. This is the first study that specifies G-protein-activator domains in insR and describes their modification by autophosphorylation.