Mitogenically Uncoupled Insulin and IGF-I Receptors of Differentiated Human Neuroblastoma Cells Are Functional and Mediate Ligand-Induced Signals

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Abstract
The SH-SY5Y human neuroblastoma cell line is differentiated in vitro with nanomolar concentrations of 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Untreated cells express insulin receptors, and both type I and type II insulin-like growth factor (IGF) receptors, as has been shown by agonist binding and immunoprecipitation studies. Via interaction with its own receptor and the IGF-I receptor, insulin induced a mitogenic response in these cells. IGF-I and IGF-II are also mitogens for SH-SY5Y cells, as shown by a transient increase of the c-fos mRNA level, ornithin decarboxylase activity, thymidine incorporation, and, finally, cell division. TPA-differentiated cells do not respond mitogenically to any of these factors, although insulin and IGF-I receptors are still present on the cell surface and remain functional, as demonstrated by ligand-stimulated autophosphorylation, actin reorganization, and c-fos induction. However, other prereplicative responses, i.e., increased ornithin decarboxylase activity and c-myc mRNA levels, cannot be induced. These phenomena, may be part of a receptor uncoupling mechanism(s). The findings are discussed in terms of differentiation stage-dependent signaling of growth factor receptors. We suggest that these receptors switch from controlling cell division in replicative neuronal cells to mediating externally controlled functions related to the differentiated neuronal phenotype.