Article

p75NTR-live or let die

Department of Medical Biochemistry, Ole Worms Allé Building. 170, Aarhus University, DK-8000C Aarhus, Denmark.
Current Opinion in Neurobiology (Impact Factor: 6.63). 03/2005; 15(1):49-57. DOI: 10.1016/j.conb.2005.01.004
Source: PubMed

ABSTRACT

During neuronal development, neurotrophins are essential factors that promote survival, differentiation and myelination of neurons. The trophic signals are relayed to the cells via binding to Trk receptor tyrosine kinases and the p75 neurotrophin receptor. Paradoxically, the p75 neurotrophin receptor also ensures rapid and appropriate apoptosis of neonatal neurons not reaching their proper targets and transmits death signals to injured neurons. Until recently, the mechanisms by which the p75 neurotrophin receptor governs these opposing functions have remained elusive. By the identification of new ligands and cytosolic interacting partners, receptor cleavage products and coreceptors, some of these mechanisms are now being unraveled. Here, we review recent progress in delineating the molecular networks that enable p75(NTR) to dictate life and death.

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    • "In contrast to their mature counterparts , proNTs induce apoptosis, growth cone collapse, and facilitate synaptic retraction by a mechanism that requires p75 NTR but is independent of Trk receptors (Lee et al., 2001; Nykjaer et al., 2004; Rö sch et al., 2005; Woo et al., 2005; Yano et al., 2009). The capacity of proNTs to induce apoptosis is considered particularly important in conditions of acute and insidious neuronal and glial cell degeneration such as spinal cord and peripheral nerve injury, seizure, and aging (Arancio and Chao, 2007; Beattie et al., 2002; Ibá n ˜ ez and Simi, 2012; Nykjaer et al., 2005; Petratos et al., 2003). "
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    ABSTRACT: Balancing trophic and apoptotic cues is critical for development and regeneration of neuronal circuits. Here we identify SorCS2 as a proneurotrophin (proNT) receptor, mediating both trophic and apoptotic signals in conjunction with p75(NTR). CNS neurons, but not glia, express SorCS2 as a single-chain protein that is essential for proBDNF-induced growth cone collapse in developing dopaminergic processes. SorCS2- or p75(NTR)-deficient in mice caused reduced dopamine levels and metabolism and dopaminergic hyperinnervation of the frontal cortex. Accordingly, both knockout models displayed a paradoxical behavioral response to amphetamine reminiscent of ADHD. Contrary, in PNS glia, but not in neurons, proteolytic processing produced a two-chain SorCS2 isoform that mediated proNT-dependent Schwann cell apoptosis. Sciatic nerve injury triggered generation of two-chain SorCS2 in p75(NTR)-positive dying Schwann cells, with apoptosis being profoundly attenuated in Sorcs2(-/-) mice. In conclusion, we have demonstrated that two-chain processing of SorCS2 enables neurons and glia to respond differently to proneurotrophins.
    Full-text · Article · Jun 2014 · Neuron
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    • "Binding of BDNF to TrkB leads to autophosphorylation of tyrosines in the intracellular domain with activation of downstream signaling pathways such as RAS/MAPK and PI3K/AKT [4], [5]. BDNF also binds low affinity receptor p75NTR which exerts diverse functions such as the regulation of cell survival and differentiation during neuronal development [6]. "
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    ABSTRACT: Tropomyosin-related receptor kinase B (TrkB) signaling, stimulated by brain-derived neurotrophic factor (BDNF) ligand, promotes tumor progression, and is related to the poor prognosis of various malignancies. We sought to examine the clinical relevance of BDNF/TrkB expression in colorectal cancer (CRC) tissues, its prognostic value for CRC patients, and its therapeutic potential in vitro and in vivo. Two hundred and twenty-three CRC patient specimens were used to determine both BDNF and TrkB mRNA levels. The expression of these proteins in their primary and metastatic tumors was investigated by immunohistochemistry. CRC cell lines and recombinant BDNF and K252a (a selective pharmacological pan-Trk inhibitor) were used for in vitro cell viability, migration, invasion, anoikis resistance and in vivo peritoneal metastasis assays. Tissue BDNF mRNA was associated with liver and peritoneal metastasis. Tissue TrkB mRNA was also associated with lymph node metastasis. The co-expression of BDNF and TrkB was associated with liver and peritoneal metastasis. Patients with higher BDNF, TrkB, and co-expression of BDNF and TrkB had a significantly poor prognosis. BDNF increased tumor cell viability, migration, invasion and inhibited anoikis in the TrkB-expressing CRC cell lines. These effects were suppressed by K252a. In mice injected with DLD1 co-expressing BDNF and TrkB, and subsequently treated with K252a, peritoneal metastatic nodules was found to be reduced, as compared with control mice. BDNF/TrkB signaling may thus be a potential target for treating peritoneal carcinomatosis arising from colorectal cancer.
    Full-text · Article · May 2014 · PLoS ONE
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    • "These results suggest that BDNF-TrkB signaling recruits and activates the positive regulators of neurite outgrowth Cdc42 and Rac1. BDNF and its protein precursor proBDNF bind to the non-specific neurotrophin receptor p75 (p75NTR), which has been shown to negatively impact cell survival and neurite outgrowth (Nykjaer et al., 2005; Blochl and Blochl, 2007). Interestingly, proBDNF-p75NTR signaling promotes growth cone collapse via downstream activation of RhoA (Sun et al., 2012). "
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    ABSTRACT: Adult neurogenesis, restricted to specific regions in the mammalian brain, represents one of the most interesting forms of plasticity in the mature nervous system. Adult-born hippocampal neurons play important roles in certain forms of learning and memory, and altered hippocampal neurogenesis has been associated with a number of neuropsychiatric diseases such as major depression and epilepsy. Newborn neurons go through distinct developmental steps, from a dividing neurogenic precursor to a synaptically integrated mature neuron. Previous studies have uncovered several molecular signaling pathways involved in distinct steps of this maturational process. In this context, the small Rho GTPases, Cdc42, Rac1, and RhoA have recently been shown to regulate the morphological and synaptic maturation of adult-born dentate granule cells in vivo. Distinct upstream regulators, including growth factors that modulate maturation and integration of newborn neurons have been shown to also recruit the small Rho GTPases. Here we review recent findings and highlight the possibility that small Rho GTPases may act as central assimilators, downstream of critical input onto adult-born hippocampal neurons contributing to their maturation and integration into the existing dentate gyrus (DG) circuitry.
    Full-text · Article · Aug 2013 · Frontiers in Synaptic Neuroscience
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