Okadaic acid (OKA), a potent inhibitor of serine phosphatases at concentrations as low as 20–25 nm, induces apoptosis of R- mouse embryo fibroblasts, which are 3T3-like cells devoid of type 1 insulin-like growth factor receptors (IGF-IRs). From R- cells, we have generated (by stable transfection) cell lines with IGF-IR numbers ranging from 0 (R- cells) to >106 receptors per cell. The wild-type IGF-IR protects R- cells from OKA-induced apoptosis, its protective effect being exquisitely dependent on the number of receptors. A small increment in wild-type receptor number (from 15 × 103 to 22 × 103 receptors/cell) is sufficient to change R--derived cells from sensitive to resistant to apoptosis. We have also studied the effect of various mutations of the IGF-IR on its ability to protect R--derived cells from OKA-induced apoptosis. Our data indicate a correlation between protection from apoptosis and the ability of the receptor to respond to insulin-like growth factor I with mitogenesis.
This work was supported by Grants GM 33694 and CA 53484 from the NIH. M. R. was supported by a grant from the Associazione Italiana per le Ricerche sul Cancro.