IndraLab
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"XREF_BIBR; XREF_BIBR Unlike the ligand induced dimerization mechanism for NGF activation of TrkA through 2:2 receptor complexes, XREF_BIBR; XREF_BIBR a ligand induced conformational change in a preformed p75NTR dimer is the likely activation mechanism, XREF_BIBR raising the question of the implications of the 2:1 NGF and p75NTR versus the 2:2 NT-3 and p75NTR complexes."
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"Decades of research have demonstrated that NGF directly activates and sensitizes TrkA-expressing sensory neurons and that NGF activation of TrkA could play a key role in the sensitization of TrkA-expressing nociceptors to mechanical, chemical and thermal stimuli (Levi-Montalcini, 1987; Lewin & Mendell, 1993; Petruska & Mendell, 2004)."
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"Together, these results indicate that NGF gene therapy can prevent neuropathy in diabetic bone marrow.We then confirmed that NGF overexpression activated the TrkA signalling in the sensory neurons, and with this aim, we analysed the cell bodies of sensory neurons located in the dorsal root ganglia (DRG)."
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"Retrovirus mediated transfer of the beta-NGF gene into NET cells activated TrkA and consistently decreased their proliferative responses to insulin like growth factor (IGF)-I, IGF-II, fibroblast growth factor-2, and epidermal growth factor (EGF), down-regulating EGF and IGF-I binding sites."
sparser
"To determine if TrkA ligand, β-NGF, can induce STAT3 phosphorylation and nuclear transport, we conducted IF followed by confocal microscopy and we showed ( xref E) that β-NGF induced TrkA activation, as indicated by p-TrkA signals (green), and STAT3 activation as indicated by nuclear p-STAT3 (red)."
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"This implicates RAS and MAPK signaling in the NB tumour suppressing effects of NGF activated TrkA receptors and PI3K/Akt/NF-kappaB without RAS and MAPK signaling in the diametrically opposed oncogenic activity of TrkAIII, which for some reason is unable to activate the RAS and MAPK pathway, despite binding Grb-2 and Frs-2 adapter proteins involved in RAS and MAPK activation [XREF_BIBR]."
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"Thus, the naked mole-rat TRPV1 protein can rescue capsaicin and heat sensitivity in Trpv1 sensory neurons with a heat-activation threshold concomitant with the heat-activation threshold of nmrTRPV1 (Smith et al., 2011) and is fully capable of NGF initiated sensitization in the mouse cellular context.Rapid TRPV1 sensitization via NGF activation of TrkA receptors can be reconstituted in human and animal-derived cell lines as well as Xenopus laevis oocytes (Bonnington and McNaughton, 2003, Prescott and Julius, 2003, Zhang et al., 2005)."
sparser
"These data on the ectopic sprouting of TrkA + sensory and sympathetic nerve fibers are interesting as they indicate how pre-emptive treatment with therapies that block NGF activation of TrkA may reduce the attendant pain, but also may block the pathologic remodeling of sensory and sympathetic nerve fibers that are themselves a major driver of chronic hypersensitivity."
sparser
"The neurotrophins NGF and NT-3 activate cell surface TrkA, which responds by recruiting MTs to detergent-resistant cell surface lipid rafts and reorganising the assembly of MTs required for neuritogenesis, axon genesis, and growth cone formation, resulting in neuronal differentiation [ xref – xref ]."
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"Similarly, elegant genetic experiments published by Miller and colleagues have shown that this mechanism is also employed during the development of SCGs; p75 cell death signaling depends on JNK, and the expression of the p53 transcription factor is downregulated by NGF induced TrkA activation in SCG axons 37."
sparser
"The results of these two additional experiments are consistent with the requirement for TrkA activation by NGF and the insufficiency of p75 binding by neurotrophins in inducing mitochondria fission and discussed on 495-501; “The concentration profile of NGF induced fission on axonal mitochondria is consistent with activation of the TrkA receptor (Kaplan et al., 1991) that activates both PI3K and Erk signaling."
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"The data summarized above demonstrates that when NGF activates its high affinity receptor TRKA in human granulosa cells of normal ovary and in epithelial cells from EOC, it acts as an indirect angiogenic factor by increasing VEGF expression and also as a direct angiogenic factor by activating TRKA in endothelial cells, therefore increasing angiogenesis in EOC."
sparser
"NGF activates TrkA receptor triggering downstream signaling pathways (Kaplan and Miller, xref ; Chao, xref ; Huang and Reichardt, xref ), while p75NTR signaling is complex (Skeldal et al., xref ), inducing both survival and apoptosis mechanisms (Salehi et al., xref ; Roux et al., xref ; Mamidipudi et al., xref )."
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"In addition, TrkA dependent cellular processes such as ERK phosphorylation, JNK phosphorylation, PARP cleavage, caspase-7 activation and caspase-8 cleavage were strongly enhanced by NGF and were significantly suppressed by SP600125, but not by wortmannin, indicating that NGF enhances TrkA dependent apoptotic signaling in a JNK dependent manner (XREF_FIG)."
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"Analysis of TRK oncogenes signal transduction, performed in NIH3T3 foci, have detected the involvement of several signal transducers recruited by the NGF stimulated NTRK1 receptor, such as Shc, PLCgamma, ERK1/2 and JNK MAP kinases (Borrello et al, 1994, manuscript in preparation)."
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"These results suggest that the trkA receptor mediates bioelectric responses to NGF and its activation inhibits amiloride-sensitive Na + transport.NGF reduces amiloride-sensitive Na + transport through a trkA/Erk1/2-mediated pathwayThe trkA receptor, when activated by NGF, can activate several intracellular signaling cascades, including the Erk1/2 signaling pathway (Segal and Greenberg 1996) ."
eidos
"Nerve growth factor ( NGF ) was studied therapeutically to activate TrkA in models of Alzheimer disease ( AD ) ( Schindowski et al ., 2008 ; Cuello et al ., 2010 ) , and ageing ( Mufson et al ., 2000 ; Bruno et al ., 2004 ; Saragovi , 2005 ) , or Down syndrome ( Sendera et al ., 2000 ; Dorsey et al ., 2006 ) , models with cholinergic deficits and memory impairment ."
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"These results suggest that simvastatin is neurotoxic and PC12 cells elicited a protective response, involving a transient activation of a Trk mediated intracellular signal transduction pathway by an autocrine secretion of NGF, although these responses did not persist against pro apoptotic signals and resulted in an apoptosis of the PC12 cells."
sparser
"PDNF might be a better therapeutic than NGF because it 1) activates both prosurvival TrkA and TrkC while NGF activates only TrkA; 2) has a unique dual prosurvival activity by directly activating TrkA and TrkC outside cells and, in the intracellular milieu, pro-survival Akt kinase xref ; 3) creates a positive TrkA signaling loop by robustly upregulating NGF; 4) has a relatively long half-life (detectable in the heart for >30 min after iv injection, see xref )."
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"NGF-induced TrkA activation initiates three main signalling cascades, the phosphatidylinositol-3-kinase (PI3K)-Akt pathway, the Ras-mitogen activated protein kinase-extracellular signal regulated kinase (Ras-MAPK-ERK) pathway, and the phospholipase C-gamma (PLC-γ) pathway [4,5,6,7]."
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"In cell fractionation studies in which 125 I-NGF is bound to PC12 cells in the cold, and the cells are washed and warmed to allow internalization of NGF bound receptors XREF_BIBR, XREF_BIBR, XREF_BIBR, NGF caused rapid internalization of TrkA into endosomes that could be recovered in organelles that emerged when cells were mechanically permeabilized by a single passage through a tight passage created by a ball whose diameter is very close to that of a surrounding cylinder."
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"On the other hand, the addition of exogenous CS-E polysaccharides into the culture medium inhibited NT-4/5-and NGF mediated TrkA activation, consistent with the mechanism that CS-E polysaccharides in solution can sequester neurotrophins away from the cell surface and prevent them from activating TrkA receptors."
sparser
"Chick ciliary ganglion neurons in culture lack TrkA receptors but express p75NTR and also fail to show NGF-dependent GSK3beta phosphorylation of MAP1B, whereas in rat superior cervical ganglion neurons in culture, NGF activation of TrkA receptors elicits GSK3beta phosphorylation of MAP1B. Finally, inhibition of TrkA receptor tyrosine kinase activity in PC12 cells and superior cervical ganglion neurons with K252a potently and dose-dependently inhibits neurite elongation while concomitantly blocking GSK3beta phosphorylation of MAP1B. These results suggest that the activation of GSK3beta by NGF is mediated through the TrkA tyrosine kinase receptor and not through p75NTR receptors."
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"Experimental studies using cultured cells have consistently supported the hypothesis that TrkA activation by NGF stimulates cell death and hinders growth in MB [47,97,98], and TrkA expression in MB is associated with neuronal differentiation, low proliferation, and apoptosis [99]."
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"25 These facts suggest that NGF mediated TrkA activation could have important roles in the regulation of transcription via hnRNP K, hnRNP C1/C2, SRSF1, SRSF3, BAF53A and TDP43; in nuclear structure via lamin B1; in protein stability via PSalpha1; and in enzymatic modification via septin-2 and PP2Acbeta in a JNK dependent manner in SK-N-MC cancer cell death signaling."
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"Modulation of NGF receptors by inhibition of p75 NTR (expressed by Muller glia) was also shown to enhance TrkA mediated survival of injured RGCs 79, indicating that targeting microglial activation and modulating neurotrophic pathway may be a potential strategy to save retinal neurons following injury."
sparser
"A sensitization mechanism based upon cFLIP sequestration was suggested by NGF stimulation of a CEP-701-sensitive binding interaction between NGF-activated TrkA and cFLIP and was confirmed by a reduction in cFLIP and increase in caspase-8 recruitment to TRAIL-activated death receptor complexes."
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"Subsequently NTRK1 becomes activated by the extracellular pool of NGF molecules, which in turn leads to NTRK1 mediated transcriptional responses (e.g. increased EGR1), as well as synergistic interaction with IL-13 in eliciting transcription and secretion of CCL26 and other mediators of the allergic response."
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"These findings not only provide the first direct experimental demonstration of trkA mediating a physiological response in an appropriate cell type, namely NGF promoted survival of embryonic neurons, but indicate that not all neurons are able to respond to a trkA mediated signal transduction event."
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"Like the tumor itself, sensory and sympathetic nerve fibers appear to be continually evolving by undergoing sprouting, degeneration and re-sprouting with disease progression and this sprouting and neuroma formation and cancer pain is in part driven by NGF activation of TrkA nerve fibers."
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"Our preliminary results (see XREF_SUPPLEMENTARY) demonstrate that chronic ECS treatment results in a robust increase in the overall level of tyrosine phosphorylation in some of the same brain regions where both NGF and TrkA were found to be upregulated (i.e., perirhinal cortex), suggesting that NGF activation of TrkA may contribute to this effect."
sparser
"Although TrkAIII influence on “Evasion of Growth Suppression” and “Immortalization” hallmarks, have yet to be described, TrkAIII influences the hallmarks of “Immune Evasion” by up-regulating MMP-9, cFLIP and Mcl-1 expression [ xref , xref , xref ]; “Tumour-associated Inflammation” through constitutive activation of the pro-inflammatory transcription factor NF-кB [ xref ]; “Invasion and Metastasis” by up-regulating MMP-9 and down-regulating TIMP-3 expression [ xref ]; “Angiogenesis” through PIP3K-mediated upregulation of MMP-9 and VEGF expression, down-regulation of TIMP-3 and thrombospondin-1 expression [ xref ] and promotion of micronuclei formation [ xref ]; “Genetic Instability” by increasing sister chromatid exchange and inducing centrosome amplification, resulting in aneuploidy [ xref ]; “Apoptosis Resistance” by up-regulating Bcl2, Bcl-xL, Mcl-1 and SOD-2 expression and partial activation of a survival-adapted UPR [ xref , xref , xref ]; “Metabolism” through ER stress-induced mitochondrial translocation, activation and PDHK1 tyrosine phosphorylation, resulting in a switch to aerobic glycolysis [ xref ]; and “Sustained Proliferation” by activating chronic PI3K/Akt in the absence RAS/MAPK signaling, inhibiting pro-differentiation signaling from NGF-activated TrkA and maintaining a tumour stem cell-like phenotype [ xref , xref ] (Schematized in Fig. xref )."
sparser
"Moreover, NGF at axon terminals must be internalized and retrogradely transported to neuron cell bodies for the NGF signal to induce phosphorylation of CREB (cAMP response element-binding protein) and to increase survival of immature neurons [ xref – xref ]; NGF-induced activation of TrkA in axon terminals was also required for survival [ xref – xref ]."
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"Compounds that can prevent NGF-mediated activation of TrkA on peripheral
nociceptors will be useful in the management of pain and those capable
of acting centrally to augment NGF-mediated activation of TrkA could
be developed as Alzheimer’s therapeutics to support the cholinergic
system.To develop TrkAIg2 domain binders, access to reproducible
structural
information is required to confirm the compound binding site."
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"XREF_BIBR, XREF_BIBR The ACTB protein, tropomyosin 3, dynein intermediate chain protein, vimentin, lamin A/C isoform 1 precursor, lamin B2, hnRNPKa and heat shock 70-kDa protein 5 have been identified as NGF mediated TrkA dependent effector proteins using a DIGE (fluorescence two-dimensional difference gel electrophoresis) proteomic analysis in SY5Y neuroblastoma cells stably expressing ectopic TrkA."
sparser
"Experimental studies using cultured cells have consistently supported the hypothesis that TrkA activation by NGF stimulates cell death and hinders growth in MB [ xref , xref , xref ], and TrkA expression in MB is associated with neuronal differentiation, low proliferation, and apoptosis [ xref ]."
sparser
"In addition, piperine decreased the expression of the NGF precursor proNGF and NGF-degrading protease matrix metalloproteinase 9, whereas it increased the expression of proNGF processing enzyme matrix metalloproteinase 7, NGF, and NGF-activated receptor TrkA in the hippocampus of KA-treated rats."
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"It was also demonstrated that the compound has at least some degree of selectivity towards RET, as it failed to increase the signaling induced by the nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) via Tropomyosin receptor kinases (Trk) TrkA and TrkB, respectively."
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"To evaluate whether the metals in the medium are essential in the TrkA signaling triggered by NGF and NGF (1-14) western blot analyses were performed in PC12 cells un-pre-treated or pre-treated 24 h before with BCS (a membrane-impermeable extracellular strong metal chelating agent), in the presence or absence of CuSO 4 and ZnSO 4."
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"Although TrkAIII-specific antibodies are not available at present, the TrkA and Y490 phosphorylated TrkA antibodies used for IF have previously been shown to recognize both TrkA and TrkAIII and the anti-Y490 phosphorylated TrkA antibody shown to recognize NGF-activated TrkA and spontaneously active TrkAIII but not their inactive counterparts by IF [19–23]."
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"Furthermore, TrkAIII expression also inhibits the differentiation inducing effects of NGF activated TrkA signaling by preventing RAS and MAPK activation, characterising TrkAIII as a potential pivotal regulator of NB cell differentiation in the presence of neurotrophins [XREF_BIBR, XREF_BIBR]."
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"We found that NGF by itself slightly increased both TrkA and p75 NTR in rafts (XREF_FIG, left plots), but after in vitro reactions that promote microtubule polymerization, p75 NTR was sorted away from rafts, while NGF and TrkA were sorted into rafts (XREF_FIG, right plots and XREF_FIG)."
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"The neurotrophins NGF and NT-3 activate cell surface TrkA, which responds by recruiting MTs to detergent resistant cell surface lipid rafts and reorganising the assembly of MTs required for neuritogenesis, axon genesis, and growth cone formation, resulting in neuronal differentiation [XREF_BIBR - XREF_BIBR]."
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"Here, we confirm that NGF stimulates SOD2 expression XREF_BIBR, XREF_BIBR, XREF_BIBR in TrkA SH-SY5Y cells (this study), adding to observations that NGF induces Ras and MAPK signalling and neuronal differentiation in TrkA SH-SY5Y cells XREF_BIBR, and suggesting that SOD2 expression in SH-SY5Y cells could be regulated differently by spontaneously active intracellular TrkAIII and NGF activated cell surface TrkA receptors."
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"In a subsequent study, we reported NGF/p38 dependent increased Tropomyosin receptor kinase (Trk) A-positive nociceptive intraepidermal nerve fiber densities (IENFDs), the activation of dermal CD68-positive dendritic cells, and CD207-positive Langerhans cell (LC) aggregations in the hind footpad skin during the period of mechanical allodynia [35, 36]."
sparser
"NGF-activated TrkA initiates survival signaling by binding to and phosphorylating on tyrosine proteins such as Shc, FRS-2, rAPS, and SH2-B that activate the Ras–PI 3-kinase and Ras–MAPK signaling pathways and PLC-γ1, which regulates protein kinase C activity and intracellular calcium levels ( xref ; xref )."
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"Since TrkA receptors in the adult hippocampus are localized in cholinergic nerve endings, it is possible to speculate that increased cholinergic tone by AChEi could drive the release of target derived NGF which could then bind to and activate presynaptic TrkA receptors in the BFCN."
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"NGF is the founding member of the polypeptide neurotrophin family, activates transmembrane tyrosine kinase receptor TrkA XREF_BIBR and is responsible for the survival and differentiation of sympathetic and dorsal root ganglion neurons, as well as other cells (neuronal and non neuronal) in both the central nervous system and the periphery XREF_BIBR."
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"NGF induced TrkA dimerization and autophosphorylation, particularly on tyrosine residues 490 and 785, signifies receptor activation and functions to trigger downstream signaling cascades, including the Ras and ERK, PLCgamma, and PI3K pathways, by recruiting signaling pathway effector proteins to the membrane (XREF_FIG)."
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"The NGF released by injured tissues activates TrkA in sensory neurons, up-regulating the neuropeptidergic signalling (by CGRP and SP) and transient receptor potential cation channel subfamily V member 1 (TRPV1), pain related molecules involved in peripheral sensitization XREF_BIBR, XREF_BIBR."
| PMC
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"Moreover, a study reported that actin depolymerization rather than polymerization is essential for internalization of NGF activated TrkA in distal axons of sympathetic neurons, in contrast to our findings that WAVE1 promoted actin polymerization is required for endocytosis of BDNF activated TrkB in dendrites of CNS neurons."
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"Data indicate that : (i) positive cholinotrophic effects of NGF required activation of both TrkA and p75NTR receptors; (ii) cAMP/RA evoked differentiation inhibited NGF effects mediated by TrkA receptors and activated its p75NTR dependent suppressing influences and (iii) a differentiation evoked decrease of mitochondrial acetyl-CoA and an elevation of mitochondrial Ca could augment impairment of cholinergic neurons by neurotoxic signals."
sparser
"Although TrkAIII-specific antibodies are not available at present, the TrkA and Y490 phosphorylated TrkA antibodies used for IF have previously been shown to recognize both TrkA and TrkAIII and the anti-Y490 phosphorylated TrkA antibody shown to recognize NGF-activated TrkA and spontaneously active TrkAIII but not their inactive counterparts by IF [ xref – xref ]."
sparser
"Our preliminary results (see xref ) demonstrate that chronic ECS treatment results in a robust increase in the overall level of tyrosine phosphorylation in some of the same brain regions where both NGF and TrkA were found to be upregulated (i.e., perirhinal cortex), suggesting that NGF activation of TrkA may contribute to this effect."
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"The keratinocytes contain various neurotransmitters and receptors like opioids, proteases, substance P (SP), nerve growth factor, neurotrophin 4, μ/κ-opioid receptors, proteinase activated receptor 2, tropomyosin-related kinase A, transient receptor potential vanilloid ion channels, and cannabinoid receptors 1 and 2 [20]."
sparser
"The downstream mediators of BDNF activation of TrkB and NGF activation of TrkA are well-characterized and include the phosphatidyl inositol-3 (PI3)-kinase (also known as Akt or protein kinase B), phospholipase C-γ1 and the ras-MAPK pathway, also known as the extracellular receptor kinase (ERK) pathway (229)."
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"In contrast to TrkA levels, we observed a significant increase in NGF mediated activation of TrkA (phosphorylated TrkA [pTrkA]/TrkA/actin) at 0 ng/ml (likely due to residual TrkA activation) and 1 ng/ml, but not 50 ng/ml (XREF_FIG), in Ret-cKO neurons compared with Ret-WT neurons."
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"Taken together, these data demonstrated that TrkA is a determinant of pancreatic adenocarcinoma chemoresistance and PI3K and Akt is a key signaling component by which NGF activation of the TrkA signal transduction pathway protects pancreatic cancer cells from chemotherapy induced cell death."
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"Thus, nerve growth factor (NGF) activates TrkA [XREF_BIBR, XREF_BIBR], brain derived neurotrophic factor (BDNF) [XREF_BIBR] and neurotrophin-4/5 (NT-4/5) [XREF_BIBR] binds to TrkB; and neurotrophin-3 (NT-3) [XREF_BIBR] reacts with TrkC, although it can also bind TrkA and TrkB with lesser affinity [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
sparser
"Similarly, elegant genetic experiments published by Miller and colleagues have shown that this mechanism is also employed during the development of SCGs; p75 cell death signaling depends on JNK, and the expression of the p53 transcription factor is downregulated by NGF-induced TrkA activation in SCG axons xref ."
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"These data on the ectopic sprouting of TrkA sensory and sympathetic nerve fibers are interesting as they indicate how pre-emptive treatment with therapies that block NGF activation of TrkA may reduce the attendant pain, but also may block the pathologic remodeling of sensory and sympathetic nerve fibers that are themselves a major driver of chronic hypersensitivity."
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"The observations that NGF activates TrkA autophosporylation on Y490, the Shc binding site, and phosphorylation and activation of Akt in neurons from Linx tEGFP and tEGFP mice suggest that ligand dependent activation of cell surface TrkA and at least some TrkA effectors occurs normally in the absence of Linx (XREF_FIG)."
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"TrkA expressing NB cells treated with NGF (which activates MAPK) increase the number and length of extended neurites and decrease cell proliferation resulting in a more mature neuronal appearing cell, while TrkB expressing NB cells treated with ligand (BDNF) increase cell proliferation without morphologic differentiation."
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"This apparently obvious approach is not as trivial as it may seem because NGF induced NTRK1 activation leads to cell type specific biological effects, such as the differentiation of neuronal cells, the apoptosis of medulloblastoma cells and the mitogenesis of non neuronal cells (Muragaki et al, 1997)."
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"Intriguingly, NGF independent activation of TrkA can be induced by various stimuli including amyloid-beta XREF_BIBR, XREF_BIBR, proteosome inhibitors such as MG-132 and lactacystin XREF_BIBR, XREF_BIBR, and dorsomorphin, a selective inhibitor of bone morphogenetic protein signaling XREF_BIBR."
sparser
"Decades of research have demonstrated that NGF directly activates and sensitizes TrkA-expressing sensory neurons and that NGF activation of TrkA could play a key role in the sensitization of TrkA-expressing nociceptors to mechanical, chemical and thermal stimuli ( xref ; xref ; xref )."
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"In line with the modulatory role of NGF on amyloid precursor protein (APP) secretory pathway (s) in NGF responsive cells, the ectopic administration of NGF stimulates the binding of its high-affinity receptor TrK kinase A (TrkA) to Amyloid Precursor Protein (APP) in in vitro cholinergic septal neurons favoring its subcellular localization in Golgi compartment -- via downregulation in phosphorylation at the threonine 668 (T668) -- which, in turn, reduces susceptibility to BACE cleavage and promotes the anti-amyloidogenic processing."
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"In the present study, we show that NGF stimulates HIV-1 replication in primary macrophages by signaling through its high-affinity receptor Tropomyosin related Kinase A (TrKA), and with the involvement of reticular calcium, protein kinase C, extracellular signal regulated kinase, p38 kinase, and nuclear factor-kappaB."
sparser
"TrkA and TrkB are differentially regulated in neuroblastoma tumor cells ( xref ) and, consistent with the differences in functional effects, the transcriptome regulated by NGF activation of TrkA is markedly different from the transcriptome regulated by BDNF activation of TrkB ( xref )."
sparser
"However, experiments in cell lines revealed that induction of the NGF-TrkA signaling produced a phenotype of dramatic suppression of cell proliferation through inhibition of cell division and pronounced intracellular vacuolization, in a way straightly dependent on NGF activation of TrkA."
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"A dipeptide mimetic of NGF loop 4, bis (N-succinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2), developed at the Zakusov Research Institute of Pharmacology, has the NGF like ability to activate TrkA receptors, but unlike NGF, GK-2 activates mainly the PI3K and AKT pathway associated with neuroprotection and has no effect on the MAPK cascade associated with hyperalgesia, the main side effect of NGF."
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"While the neurotrophin NGF stimulates TrkA in sympathetic neurons to promote axon maintenance and process outgrowth, its precursor protein ProNGF, which is elevated in the human heart after MI 77, activates the p75 neurotrophin receptor (p75NTR; also called TNF receptor super family 16, TNFRS16), to trigger axon degeneration XREF_BIBR, XREF_BIBR (XREF_FIG)."
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"NGF is known to have several different sensitizing effects on sensory neurons. xref , xref Activation of trkA by NGF can alter the responsiveness of several membrane proteins and/or ion channels (including TRPV1, sodium, calcium, or even potassium channels) by post-translational mechanisms (early sensitization)."
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"Although TrkAIII influence on " Evasion of Growth Suppression " and " Immortalization " hallmarks, have yet to be described, TrkAIII influences the hallmarks of " Immune Evasion " by up-regulating MMP-9, cFLIP and Mcl-1 expression [XREF_BIBR, XREF_BIBR, XREF_BIBR]; " Tumour associated Inflammation " through constitutive activation of the pro inflammatory transcription factor NF-kB [XREF_BIBR]; " Invasion and Metastasis " by up-regulating MMP-9 and down-regulating TIMP-3 expression [XREF_BIBR]; " Angiogenesis " through PIP3K mediated upregulation of MMP-9 and VEGF expression, down-regulation of TIMP-3 and thrombospondin-1 expression [XREF_BIBR] and promotion of micronuclei formation [XREF_BIBR]; " Genetic Instability " by increasing sister chromatid exchange and inducing centrosome amplification, resulting in aneuploidy [XREF_BIBR]; " Apoptosis Resistance " by up-regulating Bcl2, Bcl-xL, Mcl-1 and SOD-2 expression and partial activation of a survival adapted UPR [XREF_BIBR, XREF_BIBR, XREF_BIBR]; " Metabolism " through ER stress induced mitochondrial translocation, activation and PDHK1 tyrosine phosphorylation, resulting in a switch to aerobic glycolysis [XREF_BIBR]; and " Sustained Proliferation " by activating chronic PI3K and Akt in the absence RAS and MAPK signaling, inhibiting pro differentiation signaling from NGF activated TrkA and maintaining a tumour stem cell like phenotype [XREF_BIBR, XREF_BIBR] (Schematized in Fig."
sparser
"This last result is surprising because the function of SH2 domains is to bind to phosphotyrosine residues, and the fact that the SH2 domain of p85β binds to TRPV1 thus seems to imply that there must be some phosphotyrosine residues present in TRPV1. xref have shown that tyrosines in TRPV1 are phosphorylated and that the phosphorylation is enhanced when TrkA is activated by NGF."
sparser
"Furthermore, it has been demonstrated the existence of cross-talk between the signal pathways mediated by Ret and by another member of the Trk-family, the TrkA receptor, in developing sympathetic neurons, whereby increased Ret expression and phosphorylation takes place as a consequence of TrkA activation by NGF by intracellular mechanisms xref ."
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"Consistent with these results, the number of TrkA dependent dead cells stained by trypan blue was greatly increased by NGF, and this effect was significantly suppressed by SP600125, but not by wortmannin, indicating that NGF enhances TrkA dependent cancer cell death in a JNK dependent manner (XREF_FIG)."
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"However, experiments in cell lines revealed that induction of the NGF-TrkA signaling produced a phenotype of dramatic suppression of cell proliferation through inhibition of cell division and pronounced intracellular vacuolization, in a way straightly dependent on NGF activation of TrkA."
sparser
"NGF plays an inflammatory role, xref probably due to the direct action of NGF on mast cells and sensory neurones, as proposed by Woolf. xref Neurotrophins (NTs) are neurotrophic signalling polypeptides which include nerve growth factor (NGF), brain derived growth factor (BDNF), neurotrophin-3 (NT-3), NT-4/5 and NT-6, the latter apparently being specific to fish. xref The biological effects of NTs are mediated by the binding with two families of membrane receptors, the high affinity tyrosine kinase (TrK) and low affinity p75 receptor (p75NT receptor). xref TrKA is specifically activated by NGF, whereas TrKB and TrKC are primarily receptors for BDNF and NT-3 respectively. xref The physiological role of NTs in the development, maintenance and regeneration of the sympathetic and sensory nervous system has been well established xref , xref and NGF mainly induces differentiation and decreases growth rate in a variety of neoplastic cells of neurogenic and non-neurogenic origin. xref Rasi et al. demonstrated that NGF was highly expressed not only in hepatocarcinoma (HCC) but also in early preneoplastic lesions, suggesting that NGF may have a role in the progression of HCC. xref , xref We have investigated the possible role of NTs in the physiopathology of the gallbladder, especially in carcinoma specimens, together with the expression profile analysis of some tumor markers such as MIB-1 (anti Ki-67), CD34 and CA15-3 whose role has been ascertained, but not clearly defined, in previous reports. xref – xref Ki-67 expression appears to be a good diagnostic indicator for gallbladder carcinoma but not a prognostic factor for survival in patients with gallbladder carcinoma. xref Immunoreactivity for MIB-1 antigen is low in benign lesions such as chronic cholecystitis or hyperplasia when compared with gallbladder carcinoma, suggesting that epithelial hyperplasia with increased cellular proliferative activity plays an important role in carcinogenesis."
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"Moreover, NGF at axon terminals must be internalized and retrogradely transported to neuron cell bodies for the NGF signal to induce phosphorylation of CREB (cAMP response element binding protein) and to increase survival of immature neurons [XREF_BIBR - XREF_BIBR]; NGF induced activation of TrkA in axon terminals was also required for survival [XREF_BIBR - XREF_BIBR]."
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"Interestingly, the enhancement of TrkA dependent apoptotic cellular processes and cell death caused by NGF was significantly suppressed by the JNK inhibitor SP600125, but not by the PI3K inhibitor wortmannin, indicating a JNK dependent role of NGF in TrkA induced cell-death signaling (XREF_FIG and XREF_FIG)."
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"Although the signals generated by NGF stimulation of TrkA involve many of the same pathways that are stimulated by other RTKs, its more simplified endodomain structure with only two defined docking sites makes it an attractive target to devolve how individual signaling pathways are regulated in terms of downstream responses."
sparser
"NGF-induced TrkA activation initiates three main signalling cascades, the phosphatidylinositol-3-kinase (PI3K)-Akt pathway, the Ras-mitogen activated protein kinase-extracellular signal regulated kinase (Ras-MAPK-ERK) pathway, and the phospholipase C-gamma (PLC-γ) pathway [ xref , xref , xref , xref ]."
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"The downstream mediators of BDNF activation of TrkB and NGF activation of TrkA are well-characterized and include the phosphatidyl inositol-3 (PI3)-kinase (also known as Akt or protein kinase B), phospholipase C-γ1 and the ras-MAPK pathway, also known as the extracellular receptor kinase (ERK) pathway (229)."
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"NGF activated TrkA initiates survival signaling by binding to and phosphorylating on tyrosine proteins such as Shc, FRS-2, rAPS, and SH2-B that activate the Ras-PI 3-kinase and Ras-MAPK signaling pathways and PLC-gamma1, which regulates protein kinase C activity and intracellular calcium levels."
reach
"For example, activation of TrkA, TrkB or G-CSF receptor tyrosine kinases by central administration of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) or Granulocyte-Colony Stimulating Factor (G-CSF) produces hypersensitivity and pain in humans and reduces nociceptive threshold in animal models of pain."
reach
"One possible explanation might be that since NGF uniquely promotes TrkA endocytosis in nerve terminals for carrying retrograde survival signals back to neuronal soma, this process has been co-opted for local control of NGF mediated axonal growth, via mechanisms that remain to be identified."
sparser
"The activation of TrkA by wild‐type NGF or the NGF mutants was comparable in the two U2OS‐TrkA cell lines, suggesting that the phosphorylation of Y490 and Y785 on TrkA is affected equally by the different mutants, except for the second activation phase of NGF‐K95A/Q96A present in U2OS‐TrkA/p75‐SHC1 cells."
reach
"A dipeptide mimetic of NGF loop 4,
bis(N-succinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2), developed at
the Zakusov Research Institute of Pharmacology, has the NGF-like ability to
activate TrkA receptors, but unlike NGF, GK-2 activates mainly the PI3K/AKT
pathway associated with neuroprotection and has no effect on the MAPK cascade
associated with hyperalgesia, the main side effect of NGF."