The insulin receptor (IR) is a membrane-bound glycoprotein composed of alpha and beta subunits derived from a common precursor. This processing is observed for both subtypes A and B of the IR and its physiological importance is poorly understood. In order to investigate the functional consequences of the absence of IR precursor cleavage, using site-directed mutagenesis of the hIRB cDNA, we have produced two mutants replacing the sequence Arg-Lys-Arg-Arg by either His-Lys-His-Arg or Arg-Lys-Arg-Ser. These two mutants, stably expressed in CHO, were structurally and functionally characterized in comparison to the wild-type human IR. These mutations result in the production of uncleaved receptors which are expressed normally at the cell surface. These receptors bind insulin with a normal affinity and activate the tyrosine-kinase resulting in normal phosphorylation of the receptors. These uncleaved receptors can mediate both the metabolic and mitogenic effects of insulin. These results provide evidence for a fully functional uncleaved insulin receptor of the B subtype (exon 11 + ) in contrast to the uncleaved A subtype (exon 11 -) described in the literature, which shows a reduced affinity for insulin and cannot therefore correctly transduce the insulin signal.