Neurotrophin receptors, signaling

Kaplan, D. R. and Miller, F. D., Signal transduction by the neurotrophin receptors, Curr. Opin. Cell. Biol., 9, 213-212, 1997. 

Several independent laboratories have now demonstrated that both lithium and valproate (VPA) exert complex, isozyme-specific effects on the PKC (protein kinase C) signaling cascade (reviewed in [3, 5, 11-13]). Not surprisingly, considerable research has recently attempted to identify changes in the activity of transcription factors known to be regulated (at least in part) by the PKC signaling pathway - in particular the activator protein 1 (AP-1) family of transcription factors. In the CNS, the genes that are regulated by AP-1 include those for various neuropeptides, neurotrophins, receptors, transcription factors, enzymes involved in neurotransmitter synthesis, and proteins that bind to cytoskeletal elements [14]. 

Bronfman, F.C., Tcherpakov, M., Jovin, T.M., and Fainzilber, M. (2003) Ligand-induced internalization of the p75 neurotrophin receptor A slow route to the signaling endosome. J. Neurosci. 23(8), 3209-3220. 

Teng KK, Hempstead BL. 2004. Neurotrophins and their receptors signaling trios in complex biological systems. Cell Mol Life Sci 61 35-48. 

In this model system, application of the DICE system has set the basis for integration of the signaling pathways and fimctional analysis of effector proteins as well as insights into the underlying courses for the opposing phenotypes caused by activation of different neurotrophin receptors. 

NGF acting via the p75 neutrophin receptor promotes cell death during the SC injury or infection via activation of c-jun-N-terminal kinase (JNK). It has been found that neonatal p75 neurotrophin receptor mutant mice are less prone to cell death after nerve transaction. Here it is to be noted that the same neurotrophin signaling pathway may also promote survival of... 

The mechanism of action of neurotrophins has provided a challenging and formidable problem in signal tran.sduc-tion. In addition to promoting cell differentiation and survival, neurotrophins can induce cell death under certain conditions. Several mechanisms have been proposed to explain how NGF might act as a trophic factor and as a cell killer (Casaccia-Bonnefil et al., 1998). The survival and cell death properties of the receptors are dependent upon the relative ratio of receptors and the duration of the signalling events. Here we provide evidence that neurotrophin receptors exist as preformed multi-subunit complexes. Such complex formation by transmembrane receptors is likely to dictate biological responsiveness to neurotrophins. 

Fig. 1. Transitiembrane receptors for NGF. Whereas the TrkA receptor is a member of tyrosine kinase family of receptor, the p75 neurotrophin receptor belongs to the TNF superfamily of receptors. A schematic representation of the TrkA and the p75 neurotrophin receptor is shown, together with their substrates and adaptor proteins Trk adaptor proteins include FRS II (Kouhara et al., 1997) and SH2B (Qian et al., 1998). Signal transduction by the neurotrophins involves recruitment of enzymatic activities, such as phosphatidylinositol 3 kinase (PI3-K) and phospholipase C--y for TrkA (Kaplan and Stephens, 1994) and TRAF6 for p75 (Khursigara et al., 1999).

Neurotrophin Receptors Neurotrophins bind to and activate a family of receptor tyrosine kinases called Trks (pronounced tracks ). (The general structure of receptor tyrosine kinases and the Intracellular signaling pathways they activate are covered In Chapter 14.) As shown In Figure 22-28, NGF binds to TrkA BDNF, to TrkB and NT-3, to TrkC. Binding of these factors to their receptors provides a survival signal for different classes of neurons. A second type of receptor called (NTR = neurotrophin receptor) also binds to neurotrophins, but with lower affinity. However, forms heteromulti-... 

Neurotrophins (NGF brain-derived neurotrophic factor, BDNF neurotrophin-3, NT-3 NT-4 NT-6) are important regulators of neural survival, development, function, and plasticity of the vertebrate nervous system [1]. Neurotrophins generally function as noncovalently associated homodimers. They activate two different classes of receptors, through which signaling pathways can be activated, including those mediated by Ras and members of the cdc42/rac/rho G protein families, MAP kinase, PI-3 kinase, and Jun kinase cascades. 

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. 

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... 

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