Abstract
Individual neurons express receptors for several different growth factors that influence the survival, growth, neurotransmitter phenotype, and other properties of the cell. Although there has been considerable progress in elucidating the molecular signal transduction pathways and physiological responses of neurons and other cells to individual growth factors, little is known about if and how signals from different growth factors are integrated within a neuron. In this study, we determined the interactive effects of nerve growth factor, insulin-like growth factor 1, and epidermal growth factor on the activation status of downstream kinase cascades and transcription factors, cell survival, and neurotransmitter production in neural cells that express receptors for all three growth factors. We document considerable differences in the quality and quantity of intracellular signaling and eventual phenotypic responses that are dependent on whether cells are exposed to a single or multiple growth factors. Dual stimulations that generated the greatest antagonistic or synergistic actions, compared with a theoretically neutral summation of their two activities, yielded the largest eventual change of neuronal phenotype indicated by the ability of the cell to produce norepinephrine or resist oxidative stress. Combined activation of insulin-like growth factor 1 and epidermal growth factor receptors was particularly notable for antagonistic interactions at some levels of signal transduction and norepinephrine production, but potentiation at other levels of signaling and cytoprotection. Our findings suggest that in true physiological settings where multiple growth factors are present, activation of one receptor type may result in molecular and phenotypic responses that are different from that observed in typical experimental paradigms in which cells are exposed to only a single growth factor at a time.
Highlights
Bronwen Martin‡, Randall Brenneman‡, Erin Golden‡, Tom Walent‡, Kevin G
In all subsequent experiments in this study we adhered to the following concentrations of each growth factor: epidermal growth factor (EGF) and NGF, 10 ng/ml; insulin-like growth factor 1 (IGF-1) 25 nM, acknowledging that an extra variable of the growth factor concentration could potentially be considered in further studies
As there is probably a high degree of convergence of plasma membrane signals upon these signaling scaffolds, it is more likely that integration of different signals probably occurs at this point. With this concept we investigated how different, both qualitatively and quantitatively, the eventual signal output is with respect to the growth factors when they compete for the activation of the signal transduction scaffolds
Summary
COHERENT PATTERNS OF INTERACTION CONTROL MULTIPLE LEVELS OF MOLECULAR AND PHENOTYPIC RESPONSES*□S. There has been considerable progress in elucidating the molecular signal transduction pathways and physiological responses of neural cells to individual growth factors, it is not known how signals from different growth factors are integrated within an individual cell. One cell type that has provided a valuable model for the elucidation of neurotrophic factor signal transduction mechanisms is PC12 pheochromocytoma cells generated by Greene and Tischler [13] These cells respond to NGF by differentiating into a neuron-like phenotype characterized by cessation of cell division, extension of neurites, acquisition of excitable membrane properties, and the production of the monoamine neurotransmitters dopamine and norepinephrine [13,14,15,16]. Our findings reveal distinctly different qualitative and quantitative signaling patterns and phenotypic responses generated by growth factors when they stimulate neural cells in the presence of other growth factors
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