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 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.
Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Jeremie
J
Boucher
Yazmin
Y
Macotela
Olivier
O
Bezy
Marcelo A
MA
Mori
Kristina
K
Kriauciunas
C Ronald
CR
Kahn
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015153:Blotting, Western; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D016877:Oxidants / Q000494:pharmacology; D010770:Phosphotransferases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D016877:Oxidants; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I; D006861:Hydrogen Peroxide; D010770:Phosphotransferases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin