Neurotrophin receptors, signaling pathways

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. 

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]. 

Chao, M. V. (2003). Neurotrophins and their receptors A convergence point for many signalling pathways. Nature Rev. Neurosci. 4, 299-309. 

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... 

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-... 

Simons K, Ikonen E (2000) How cells handle cholesterol Science 290 1721-1726 Skaper SD (2008) The biology of neurotrophins, signalling pathways, and functional peptide mimetics of neurotrophins and their receptors. CNS Neurol Disord Drug Targets 7 46-62 Strauss KI, Narayan RK, Raghupathi R (2004) Common patterns of bcl-2 family gene expression in two traumatic brain injury models. Neurotox Res 6 333-342 Sun D, Newman TA, Perry VH, Weller RO (2004) Cytokine-induced enhancement of autoimmune inflammation in the brain and spinal cord implications for multiple sclerosis. Neuropathol Appl Neurobiol 30 374-384... 

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. 

Neurotrophin-Trk receptor complexes are internalized and retrogradely transported from distal axons to the neuronal cell body where they signal to the soma to mediate target-dependent survival, growth and gene expression. The neurotrophin-Trk receptor complex is internalized by four mechanistically diverse and highly regulated pathways macropinocytosis clathrin-mediated endocytosis caveolae-mediated endocyto-sis and Pincher-mediated endocytosis. The kinase activity of Trk is probably required for receptor internalization. 

Trophic factors exemplified by NGF and its family members, ciliary neurotrophic factor (CNTF) and glial derived neurotrophic factor (GDNF) all utilize increased tyrosine phosphorylation of cellular substrates to mediate neuronal cell survival. Actions of the NGF family of neurotrophins are not only dictated by ras activation through the Trk family of receptor tyrosine kinases, but also a survival pathway defined by phosphatidylinositol-3-kinase activity (Yao and Cooper, 1995), which gives rise to phosphoinositide intermediates that activate the serine/ threonine kinase Akt/PKB (Dudek et al., 1997). Induction of the serine-threonine kinase activity is critical for cell survival, as well as cell proliferation. Hence, for many trophic factors, multiple proteins constitute a functional multisubunit receptor complex that activates rai-depen-dent and ras-independent intracellular signaling. 

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