An additional way by which estrogen may interact with the neurotrophins is through reciprocal regulation at the level of signal transduction. Convergence or cross-coupling of estrogen and neurotrophin signaling pathways (receptor cross-talk) may lead to nuclear end- points that regulate the same broad array of growth-associated and cytoskeletal genes related to neuronal differentiation and neurite growth. Cross-coupling of ERs with growth-factor signaling pathways has been shown in non-neural estrogen target tissues and does not involve binding to DNA (reviewed in refs. 67 and 111).
The potential for cross-coupling of the estrogen and neurotrophin signaling pathways in the developing brain is suggested by our recent studies, which provide the first example in nervous tissue that estrogen elicits rapid and prolonged tyrosine phosphorylation of both ERK1 and ERK2 (p44 and p42 MAP kinase isoforms, respectively) (48,49). Acti vation of the ERKs in PC12 cells by EGF and IGF-1, for example, is very transient, a pattern that is associated with cell proliferation (87). Prolonged activation of ERK1 and ERK2, as elicited by NGF in PC12 cells, on the other hand, has been found to lead to neuronal differentiation (84,86,95,97-99). The prolonged time-course of ERK activation, which follows estrogen exposure, is consistent with its observed differentiative actions with respect to neurite growth and differentiation (1,6-8) (Fig. 1). Estrogen-induced tyrosine phosphorylation of ERK in the cerebral cortex occurred within 5 min, became maximal at 30 min, and persisted for at least 4 h. Thirty minute pulses of the neurotrophins NGF-, BDNF-, NT-3-, and NT-4/5-induced tyrosine phosphorylation of ERK1 and ERK2 in the cortical explants to levels that were qualitatively and quantitatively similar to those following comparable exposure to estrogen. There were no additive effects, suggesting that the cells responding to each ligand were the same and not additional ER-containing subsets. Because ERK2 (and possibly ERK1) translocate to the cell nucleus (97-99), convergence or cross-coupling of the estrogen and neurotrophin receptor systems provides novel and unconventional signaling pathways to the nucleus to mediate estrogen and neurotrophin actions in the developing brain. Confirmation of estradiol-induced activation of the phosphorylated ERK, a process that is required for nuclear translocation, was established with the in-gel kinase assay, utilizing myelin basic protein (MBP) as the substrate for ERK activity (49). The E-induced, tyrosine phosphorylated ERKs were much more active in their ability (ERK2 > ERK1) to phosphorylate MBP as a substrate than the untreated controls.
The ability of estradiol to tyrosine phosphorylate and activate a component of the MAP kinase cascade (ERK) represents a novel finding in the CNS. This observation supports the idea of alternative pathways for estrogen action in the brain, which could explain both the rapid effects of estrogen and the regulation of non-ERE-containing genes. Protein tyrosine phosphorylation represents a nongenomic way by which estrogen may elicit direct effects in its target neurons. Ligand-activation of tyrosine kinases is a property shared by several membrane growth factor receptors. In some instances, the stimulated kinase is intrinsic to the receptor molecule, e.g., the trk(90) and EGF receptors (64). In other cases, ligand-activated tyrosine kinases such as src have been described that are not intrinsic to membrane receptors, but appear functionally associated with the ER (40,63,65). Membrane estrogen-binding sites could interact rapidly with the steroid and, in neurons where estrogen and neurotrophin receptors co-localize, perhaps activate contiguous tyrosine kinases.
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