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Molecular Biology and Genetics |
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [A. M., G. R., M. N., K. R., B. V., M. D., R. B.], and Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60637 [E. E., M. R. R.]
The type I insulin-like growth factor receptor (IGF-IR) is known to send two seemingly contradictory signals inducing either cell proliferation or cell differentiation, depending on cell type and/or conditions. H19-7 cells are rat hippocampal neuronal cells immortalized by a temperature-sensitive SV40 large T antigen that grow at 34°C in epidermal growth factor or serum but differentiate at 39°C when induced by basic fibroblast growth factor. At 39°C, expression of the human IGF-IR in H19-7 cells induces an insulin-like growth factor (IGF) I-dependent differentiation. We have investigated the domains of the IGF-IR required for differentiation of H19-7 cells. The tyrosine 950 residue and serines 1280–1283 in the COOH terminus of the receptor are required for IGF-I-induced differentiation at 39°C, although they are dispensable for IGF-I-mediated growth at 34°C. Both domains have to be mutated to inactivate the differentiating function. The inability of these mutant receptors to induce differentiation correlates with mitogen-activated protein kinase activation. In contrast, inhibitors of phosphatidylinositol 3'-kinase have no effect on IGF-I-mediated differentiation of H19-7 cells, although they do inhibit the mitogenic response.
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