A Kinase-Independent Role for Unoccupied Insulin and IGF-1 Receptors in the Control of Apoptosis

Insulin and insulin-like growth factor 1 (IGF-1) act as anti-apoptotic hormones. We found that, unexpectedly, double knockout (DKO) cells that lacked both insulin and IGF-1 receptors (IR and IGF1R, respectively), were resistant to apoptosis induced through either the intrinsic or extrinsic pathway. This resistance to apoptosis was associated with decreased abundance of the pro-apoptotic protein Bax and increases in abundance of the anti-apoptotic proteins Bcl-2, Bcl-xL, XIAP, and Flip. These changes in protein abundance involved primarily post-transcriptional mechanisms. Restoration of the insulin or IGF-1 receptor to DKO cells also restored their sensitivity to apoptosis. Notably, expression of a catalytically inactive mutant form of the insulin receptor also restored susceptibility to apoptosis. Thus, the insulin and IGF-1 receptors have bidirectional roles in the control of cell survival and can be viewed as previously-unidentified dependence receptors. Insulin and IGF-1 binding stimulates receptor tyrosine kinase activity and blocks apoptosis, whereas unliganded insulin and IGF-1 receptors, acting through a mechanism independent of their catalytic activity, exert a permissive effect on cell death.