Insulin receptor isoforms differently regulate cell proliferation and apoptosis in the ligand‐occupied and unoccupied state

The insulin receptor (IR) presents two isoforms (IR‐A and IR‐B) that differ for the α‐ subunit C‐terminal. Both isoforms are expressed in all human cells albeit in different proportions, yet their functional properties‐when bound or unbound to insulin‐are not well characterized. From a cell model deprived of the Insulin‐like Growth Factor 1 Receptor (IGF1‐R) we therefore generated cells exhibiting no IR (R‐shIR cells), or only human IR‐A (R‐shIR‐A), or exclusively human IR‐B (RshIR‐B) and we studied the specific effect of the two isoforms on cell proliferation and cell apoptosis. In the absence of insulin both IR‐A and IR‐B similarly inhibited proliferation but IR‐B was 2–3 fold more effective than IR‐A in reducing resistance to etoposide‐induced DNA damage. In the presence of insulin, IR‐A and IR‐B promoted proliferation with the former significantly more effective than the latter at increasing insulin concentrations. Moreover, only insulin‐bound IR‐A, but not IR‐B, protected cells from etoposide‐induced cytotoxicity. In conclusion, IR isoforms have different effects on cell proliferation and survival. When unoccupied, IR‐A, which is predominantly expressed in undifferentiated and neoplastic cells, is less effective than IR‐B in protecting cells from DNA damage. In the presence of insulin, particularly when present at high levels, IR‐A provides a selective growth advantage.