Different Effects of the Insulin Receptor Isoforms on 32D Cell Growth and Differentiation

The Insulin Receptor (IR) mediates metabolic, mitogenic and differentiation effects. IR exists in two isoforms (IR-A and IRB) generated by alternative splicing of exon 11. IR-A and IR-B have different binding characteristics and activate partially different intracellular pathways. IR-A, but not IR-B, binds with high affinity IGF-2, a potent mitogenic and anti-apoptotic cytokine. IR-B is the prevalent isoform expressed in differentiated cells while IR-A is predominant in fetal and cancer cells. In this study, to evaluate the role of IR isoforms in cell growth and differentiation via IRS-3, a recognized mediator of cell differentiation, we co-transfected 32D murine hemopoietic cells with IRS-3 and either IR-A or IR-B. Both isoforms, when activated by insulin, were able to activate cell growth and differentiation programs even in the absence of IL-3, an absolute requirement for 32D cell survival. IR-B was much more effective than IR-A for both functions. IGF-2, although activating IR-A as expected, was not able to stimulate growth via IRS-3 and only minimally differentiation. Finally, to stimulate growth via IRS-3 insulin required for both isoforms the activation of both the ERK and the p70S6K pathways, while to stimulate differentiation the activation of only one pathway was required. In conclusion, via IRS-3, IR-B is much more active than IR-A and IGF-2 has no biological effect even when activating IR-A.