Growth Factor Signals in Neural Cells

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.Numerous growth factors have been identified that influence the survival and plasticity of neurons, including the neurotrophins (NGF, 2 brain-derived neurotrophic factor, NT-3, and NT-4), basic fibroblast growth factor, insulin-like growth factor 1 (IGF-1), and epidermal growth factor (EGF). These different factors activate receptors with intrinsic tyrosine kinase activity, which then engage downstream kinase cascades, resulting in the activation of transcription factors. For example, NGF activates the TrkA receptor that engages the Raf-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway resulting in activation of transcription factors, including AP1 (1-3); IGF-1 activates the IGF-1 receptor that is coupled to phosphatidylinositol trisphosphate kinase, Akt kinase, and forkhead transcription factors of the FOXO family (4, 5); and EGF receptors engage the Raf-MEK-ERK pathway (6, 7). Many neural cells express receptors for multiple growth factors, each of which induce similar effects on the survival, differentiation, and function of the cells. Although there has been considerable progress ...

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