Research ArticleDependence Receptors

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

Sci. Signal.  07 Dec 2010:
Vol. 3, Issue 151, pp. ra87
DOI: 10.1126/scisignal.2001173

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Signaling Death as Well as Survival

The hormone insulin and the related insulin-like growth factor 1 (IGF-1) are known for their effects in promoting cell growth and survival. Unexpectedly, Boucher et al. found that brown preadipocyte cell lines engineered to lack both the insulin receptor (IR) and the IGF-1 receptor (IGF1R) were resistant to programmed cell death (apoptosis) in response to various stimuli when compared to cells expressing either or both receptors. Analyses of the effects of introducing receptors into these resistant cells revealed that, in contrast to their role in transducing trophic signals from insulin and IGF-1, the ability of IR and IGF1R to restore sensitivity to apoptosis did not depend on their catalytic activity. Thus, IR and IGF1R appear to act as dependence receptors, a family of receptors that mediate trophic signals when bound by ligand, and signals permissive for apoptosis in the absence of ligand.

Abstract

Insulin and insulin-like growth factor 1 (IGF-1) act as antiapoptotic 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 the extrinsic pathway. This resistance to apoptosis was associated with decreased abundance of the proapoptotic protein Bax and increases in abundance of the antiapoptotic proteins Bcl-2, Bcl-xL, XIAP, and Flip. These changes in protein abundance involved primarily posttranscriptional mechanisms. Restoration of IR or IGF1R to DKO cells also restored their sensitivity to apoptosis. Notably, expression of a catalytically inactive mutant form of the IR also restored susceptibility to apoptosis. Thus, IR and IGF1R have bidirectional roles in the control of cell survival and can be viewed as dependence receptors. Insulin and IGF-1 binding stimulates receptor tyrosine kinase activity and blocks apoptosis, whereas unliganded IR and IGF1R, acting through a mechanism independent of their catalytic activity, exert a permissive effect on cell death.

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