Growth factors neurotrophin

J.S., Chute, H.T., Matheson, C., Carnahan, J, Louis, J.-C Yan, Q Welcher, A.A., Rosenfeld, R., 1994. Formation of heterodimers from three neurotrophins, nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor. J. Biol. Chem. 269, 27833-27839. 

The relative ratios of anti- and pro-apoptotic Bcl-2-family proteins dictate the ultimate sensitivity to or resistance of cells to various apoptotic stimuli, including hypoxia, radiation, anticancer drugs, oxidants, Ca2+ overload, ceramide, and growth-factor/neurotrophin deprivation [25]. 

The best characterized family of MAPKs in the brain are the extracellular signal-regulated protein kinases (ERKs) that are activated by the neurotrophins and related growth factors (Fig. 23-4) [14,15]. The MAPK kinases responsible... 

CREB is also phosphorylated on serine 133 by stimulation of growth factor signaling cascades [63]. This occurs via a complex pathway involving MAPK cascades (Fig. 23-9). Thus, as outlined earlier, nerve growth factor and related neurotrophins that act on receptor tyrosine kinases lead to the successive activation of Ras, Raf, MEK and ERK. Activated ERK then phosphorylates and activates a serine-threonine kinase, RSK, particular subtypes of which directly activate CREB via the phosphorylation of serine 133. 

Neuronal survival and differentiation are regulated by many factors including neurotrophins and the Trk family of RPTKs. The prototype neurotrophin, nerve growth factor (NGF), promotes the survival of neurons during a period of programmed cell death in embryonic and early postnatal developmental stages. It is a target-derived neurotrophic factor that modulates the functions of the... 

Tyrosine phosphorylation plays an important role in synaptic transmission and plasticity. Evidence for this role is that modulators of PTKs and PTPs have been shown to be intimately involved in these synaptic functions. Among the various modulators of PTKs, neuro-trophins have been extensively studied in this regard and will be our focus in the following discussion (for details of growth factors, see Ch. 27). BDNF and NT-3 have been shown to potentiate both the spontaneous miniature synaptic response and evoked synaptic transmission in Xenopus nerve-muscle cocultures. Neurotrophins have also been reported to augment excitatory synaptic transmission in central synapses. These effects of neurotrophins in the neuromuscular and central synapses are dependent on tyrosine kinase activities since they are inhibited by a tyrosine kinase inhibitor, K-252a. Many effects of neurotrophins on synaptic functions have been attributed to the enhancement of neurotransmitter release BDNF-induced increase in neurotransmitter release is a result of induced elevation in presynaptic cytosolic calcium. Accordingly, a presynaptic calcium-depen-dent phenomenon - paired pulse facilitation - is impaired in mice deficient in BDNF. 

TABLE 27-2 Neurotrophin targets Nerve growth factor... 

The neurotrophins interact with two distinct cell surface receptor species [5,6,9] (Fig. 27-2). The neurotrophins bind to the Trk family of receptors, which serve as the principal signal transducer for this class of growth factors. The Trk receptors comprise a small, highly related family of molecules that possess an extracellular ligand binding domain that selectively interacts with the individual neurotrophin species. Trk A specifically binds NGF, TrkB interacts with BDNF and NT4/5, and TrkC preferentially binds NT3. Importantly, the Trk receptors have an intracellular tyrosine kinase domain that is activated upon neurotrophin binding. The kinase domains of the Trk family members are highly conserved and the Trks differ mainly in the structure of their extracellular domains. Trk receptor expression is limited to neurons and the... 

FIGURE 2 7-2 Neurotrophin receptors. Neurotrophin family members bind specifically to cognate Trk receptors. The low affinity neurotrophin receptor, p75, promiscuously binds all neurotrophins. BDNF, brain-derived neurotrophic factor NGF, nerve growth factor NT, neurotrophin. 

The receptor for NGF is TrkA, a 140 kDa cell surface protein that specifically binds NGF, but not other neurotrophins [5, 6, 9]. TrkA is expressed on the neuronal cell body and on neuronal processes. In its action as a target-derived trophic factor, NGF is secreted within the target organ and it then binds to TrkA receptors present on the growing neuronal process or synapse. The NGF-TrkA complex is then internalized and subsequently translocated to the cell body by retrograde axonal transport. In those cells that respond to NGF through autocrine or paracrine mechanisms, the growth factor can bind to any of the widely distributed TrkA molecules on the neuronal membrane. 

Barrett GL, Georgiou A, Reid K, Bartlett PF, Leung D. 1998. Rescue of dorsal root sensory neurons by nerve growth factor and neurotrophin-3, but not brain-derived neurotrophic factor or neurotrophin-4, is dependent on the level of the p75 neurotrophin receptor. Neuroscience 85 1321-1328. 

Neurotrophic factors constitute a group of cytokines that regulate the development, maintenance and survival of neurons in both the central and peripheral nervous systems (Table 7.9). While the first member of this family (nerve growth factor, NGF) was discovered more than 50 years ago, it is only in the last decade that the other members have been identified and characterized. The major sub-family of neurotrophic factors are the neurotrophins. 

Most neurotrophin-sensitive cells express two receptor types on their surface a high-affinity receptor, which appears to mediate most/all of the biological actions of the neurotrophins, and a low-affinity receptor. The high-affinity receptors are all members of a family of tyrosine kinases (the Trks). They are similar to the receptors of many other growth factors, but are expressed almost exclusively on neuronal tissue. 

Kwon, Y. (2002). Effect of neurotrophic factors on neuronal stem cell death. J. Biochem. Mol. Biol. 35(1), 87-93. Raffioni, S. et al. (1993). The receptor for nerve growth factor and other neurotrophins. Ann. Rev. Biochem. 62, 823-850. Sofroniew, M. et al. (2001). Nerve growth factor signalling, neuroprotection and neural repair. Ann. Rev. Neurosci. 24, 1217-1281. 

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