Insulin receptor transmembrane signaling: evidence for an intermolecular oligomerization mechanism of activation.

To evaluate the mechanism of ligand activation of the insulin receptor we have generated mutant receptor cDNAs which encode proteins with oligopeptide linkers between the carboxy terminus of the extracellular domain and the transmembrane domain of the molecule. Mutant cDNAs encoding a rigid alpha helical insert (HIR NQDVD) or a flexible polyglycine insert (HIR G12) were expressed in CHO Kl cells. Both basal and insulin stimulated autophosphorylation in vitro and in vivo of the expressed receptors were indistinguishable from those of wild type receptor expressed in the same cells. These findings suggest that ligand binding can activate the insulin receptor by an intermolecular dimerization mechanism.