All the neurotrophins bind with high affinity to members of a family of receptor tyrosine kinases, the Trk family. The events leading to signal transduction include:
• binding of neurotrophin to the appropriate Trk receptor (in general, NGF binds to TrkA, BDNF and NT4 to TrkB, and NT3 to TrkC);
• receptor homodimerization;
• autophosphorylation of the tyrosine kinase domains of the bound receptors;
• activation of various intracellular signaling molecules that are associated with the receptor.
The cascade of intracellular signal transduction of neurotrophins follows the following pathway:
1. binding to their specific Trk receptor and promotion of the formation of a Trk-Shc-Grb2-Sos complex;
2. activation of the low-molecular-weight G protein Ras;
3. Ras activation then allows transmission of signals to other downstream pathways.
The most prominent is the MAP kinases cascade following the steps:
1. Ras activates Raf kinase, which phosphorylates and activates MEK.
3. MAP, when activated by MEK, becomes proline-directed, which means that the kinase phosphorylates serine or threonine residues neighboring prolines. One direct substrate is the protein kinase p90rsk.
Importantly, activation of MAP kinases and rsk causes their translocation to the nucleus where a number of transcription factors can be phosophrylated, such as the immediate early genes c-fos and c-jun as well as the delayed-response genes like CREB (cAMP-response element-binding protein (see Fig. 4.40).
The biological effects are long-lasting and induce changes in gene expression. Two further pathways are activated:
• The phospolipase C (PLCy) pathway, which generates DAG and IP3. The consequences of PLC activation are increase in intracellular calcium, pH, cytoske-letal responses and transcriptional changes.
• Phospatidylinositol-3 kinase (PI-3K), which catalyzes the production of phos-phoinositides. They in turn activate the protein kinase Akt, which leads to the activation of pathways necessary for growth factor-mediated survival.
Thus, there are many substrates of Trk activation in both the cytoplasm and nucleus, including other protein kinases, cytoskeletal elements, tyrosine hydroxylase and transcription factors.
Two TrkA isoforms are known, which differ in their extracellular domain. Both isoforms appear to have similar biological properties, but they differ in their expression pattern. One isoform is expressed in cells of non-neuronal origin and the other (containing a VSFSPV sequence in the extracellular domain) is primarily expressed in neuronal cells. TrkA, which serves as a receptor for NGF, has been found in NGF-responsive cells, including sympathetic neurons, small spinal sensory neurons of the dorsal root ganglion (DRG) and basal fore-brain cholinergic neurons.
TrkB is a receptor for BDNF and NT-4; and it is widely expressed in the peripheral and central nervous systems. Beside the full-length TrkB receptor, TrkB isoforms are known, having the same extracellular and transmembrane domains but lacking a tyrosine kinase catalytic domain.
At least four different isoforms of the TrkC receptor have been described. These isoforms differ from the canonical TrkC tyrosine kinase by the presence of 14, 25, or 39 additional amino acid residues in the middle of their kinase catalytic domains. Expression of TrkC, the main receptor for NT-3, has been documented in cells responsive to this neurotrophin including, among others, large spinal sensory neurons, motor neurons, noradrenergic neurons of the locus coeruleus and neurons of the substantia nigra.
Fig. 4.40 Schematic drawing of the most important pathways of trk signaling. Upon NGF binding to two trk molecules, homo-dimers are formed which allow each trk molecule to phosphorylate tyrosine residues on its partners. This phosphorylation creates specific binding sites for PI-3, PLC-y and Shc. Recruitment of these proteins into the complex initiates the different indicated signaling cascades.
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