Two alternatively spliced forms of the human insulin-like growth factor I receptor have distinct biological activities and internalization kinetics.

Two alternatively spliced human insulin-like growth factor I (IGF I) receptor mRNA transcripts have been described that differ by three nucleotides (CAG) starting at position 2829. This results in an amino acid coding sequence change from Thr-Gly to Arg in the extracellular portion of the receptor beta subunit. To investigate the functional significance of this sequence difference, we obtained full-length cDNAs for the CAG+ and CAG- receptor forms, transfected CHO cells, and isolated multiple clones expressing approximately equal numbers of receptors (0.57-0.73 x 10(6) receptors/cell). The two receptors bound IGF I with similar affinity (Kd approximately 1.7 nM), but the CAG- form exhibited an approximately 2-fold increase in IGF I stimulation of receptor autophosphorylation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, thymidine incorporation, and IRS-1-associated phosphatidylinositol 3-kinase activity. In contrast to its higher signaling activity, the rate of receptor-mediated internalization of IGF I by the CAG-receptor was decreased by 50% in comparison with the CAG+ receptor. We conclude that proteins corresponding to the two alternatively spliced human IGF I receptor transcripts are biologically active, but have distinct signaling properties. These experiments further indicate a previously unrecognized role for the extramembranous portion of the beta subunit in receptor signaling and internalization.