Neurotrophin Signal Transduction Cascades

Signals from polypeptide growth and trophic factors such as the neurotrophins are propagated to the nucleus by an essentially linear flow of sequential protein phosphorylation and dephosphorylation events. These second messenger enzyme cascades, which involve both tyrosine and serine/threonine kinases and phosphatases, serve to funnel, amplify, and propagate signals generated at the cell surface into complex biological responses, including the regulation of target transcription factors such as CREB and Elk and the induction of immediate early genes such as c-fos and c-jun (83-87). Virtually all that is known about neurotrophin signaling in neural tissue is derived from studies of nerve growth factor (NGF), the prototypical neurotrophin, in PC12 cells, a cell line derived from a rat pheochromocytoma and prototypical NGF target (88). As illustrated in Fig. 2, NGF treatment of PC12 cells elicits dimerization of trkA and activates its catalytic src-homology1 (SH1) domain, resulting in autophosphorylation of trkA on tyrosine residues (89-92). Tyrosine autophosphorylation regulates interactions of the activated trkA with multiple intracellular proteins with src-homology2 (SH2) domains that either function as enzymes (kinases), such as phospholipase C-y1 (PLC-y1) and c-src, or as docking proteins, such as Shc and Grb2. Shc and Grb2 with the glutamyl transpeptidase/gel diffusion precipitin (GTP/GDP) exchange protein SOS connect activated trkA to the authentic signaling enzyme p21Ras. Ras, a small guanine nucleotide-binding protein, then activates members of the MAP kinase cascade by sequential phosphorylation on tyrosine or serine/threonine residues. The MAP kinase cascade is triggered by Ras activation of the cell-type specific Raf family (93, 94) (b-Raf in PC12 cells; c-Raf in sympathetic neurons; b- and/or c-Raf in the CNS?); followed by activation of MAP Kinase kinase, or MEK [MAP kinase/extracellular-regulated kinase (ERK) Kinase kinase], then MAP Kinase (MAPK), or ERK, which phosphorylates other kinases such as p90Rsk or transcription factors (95). Phosphorylated ERK (ERK2 in particular) and Rsk both translocate to the nucleus and are the means by which growth factor signaling regulates transcription. The MAP kinase cascade and suc-associated neurotrophic factor-induced tyrosine-phosphorylated target (SNT) (96), a parallel, growth factor-and differentiation-specific pathway, form two major growth factor signaling pathways whose prolonged activation is necessary but not sufficient for PC12 neuronal differentiation (84,86,97-99). Neurotrophin signaling pathways in the CNS, on the other hand, are very ill-defined.

Fig. 2. Some trkA signaling cascades activated by NGF. In PC12 cells, treatment with NGF, the prototypical neurotrophic elicits dimerization of trkA and activates its catalytic ire-homology1 (SH1) domain, resulting in autophosphorylation of trkA on tyrosine residues. Autophosphorylation regulates interactions of the activated trkA with multiple intracellular proteins with SH2 domains that either function as enzymes (kinases), such as PLC-y1 and c-sre, or as docking proteins, such as Shc and Grb2. Shc and Grb2 with the GTP/GDP exchange protein SOS connect activated trkA to the authentic signaling enzyme p21Ras. Ras then activates members of the MAP kinase cascade, b-Raf, MEK, and ERK (MAPK) by sequential phosphorylation on tyrosine, serine/threonine residues. ERK then phosphorylates other kinases such as Rsk, and the phosphorylated ERKs and Rsk both translocate to the nucleus to regulate immediate early and late response genes and transcription factors. The MAP kinase cascade and SNT, a parallel, growth factor- and differentiation-specific pathway, form two major growth factor signaling pathways whose prolonged activation is necessary but not sufficient for PC12 neuronal differentiation.

Fig. 2. Some trkA signaling cascades activated by NGF. In PC12 cells, treatment with NGF, the prototypical neurotrophic elicits dimerization of trkA and activates its catalytic ire-homology1 (SH1) domain, resulting in autophosphorylation of trkA on tyrosine residues. Autophosphorylation regulates interactions of the activated trkA with multiple intracellular proteins with SH2 domains that either function as enzymes (kinases), such as PLC-y1 and c-sre, or as docking proteins, such as Shc and Grb2. Shc and Grb2 with the GTP/GDP exchange protein SOS connect activated trkA to the authentic signaling enzyme p21Ras. Ras then activates members of the MAP kinase cascade, b-Raf, MEK, and ERK (MAPK) by sequential phosphorylation on tyrosine, serine/threonine residues. ERK then phosphorylates other kinases such as Rsk, and the phosphorylated ERKs and Rsk both translocate to the nucleus to regulate immediate early and late response genes and transcription factors. The MAP kinase cascade and SNT, a parallel, growth factor- and differentiation-specific pathway, form two major growth factor signaling pathways whose prolonged activation is necessary but not sufficient for PC12 neuronal differentiation.

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