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Moses V Chao - One of the best experts on this subject based on the ideXlab platform.
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Neurotrophin Signaling in Development
Handbook of Cell Signaling, 2010Co-Authors: Katrin Deinhardt, Moses V ChaoAbstract:Publisher Summary This chapter deals with new views concerning ligand–Receptor interactions, signal transduction, and retrograde transport in the nervous system, and discusses the roles of both mature and pro-neurotrophins. It reviews the role of the neurotrophin system in development. The neurotrophins, which include nerve growth factor (NGF), brain-derived growth factor (BDNF), NT-3, and NT-4, represent an important family of trophic factors that are essential for survival of selective populations of neurons during different developmental periods. The neurotrophic hypothesis postulates that during nervous system development, neurons approaching the same final target compete for limited amounts of target-derived trophic factors. In this way, the nervous system moulds itself to maintain only the most competitive and appropriate connections. Neurotrophins exert their cellular effects through the actions of two different Receptors: the tropomyosin-related kinase (Trk) Receptor tyrosine kinase and the p75 neurotrophin Receptor (p75NTR), a member of the tumor necrosis factor (TNF) Receptor superfamily. Finally, the role of neurotrophins and their Receptors is not confined to the nervous system, but is instead increasingly recognized in non-neuronal tissues.
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activation of Trk neurotrophin Receptors by glucocorticoids provides a neuroprotective effect
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Freddy Jeanneteau, Michael J Garabedian, Moses V ChaoAbstract:Glucocorticoids (GCs) display both protective and destructive effects in the nervous system. In excess, GCs produce neuronal damage after stress or brain injury; however, the neuroprotective effects of adrenal steroids also have been reported. The mechanisms that account for the positive actions are not well understood. Here we report that GCs can selectively activate Trk Receptor tyrosine kinases after in vivo administration in the brain and in cultures of hippocampal and cortical neurons. Trk Receptors are normally activated by neurotrophins, such as NGF and brain-derived neurotrophic factor, but the activation of Trk Receptors by GCs does not depend on increased production of neurotrophins. Other tyrosine kinase Receptors, such as EGF and FGF Receptors, were not activated by GCs. The ability of GCs to increase Trk Receptor activity resulted in the neuroprotection of neurons deprived of trophic support and could be modulated by steroid-converting enzymes. Pharmacological and shRNA experiments indicate that Trk Receptor activation by GCs depends on a genomic action of the GC Receptor. The ability of GCs to promote Trk Receptor activity represents a molecular mechanism that integrates the actions of GCs and neurotrophins.
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cell survival through Trk neurotrophin Receptors is differentially regulated by ubiquitination
Neuron, 2006Co-Authors: Juan Carlos Arevalo, Rithwick Rajagopal, Zheyu Chen, Janelle C Waite, Mercedes Beyna, Moses V ChaoAbstract:Specificity of neurotrophin factor signaling is dictated through the action of Trk Receptor tyrosine kinases. Once activated, Trk Receptors are internalized and targeted for degradation. However, the mechanisms implicated in this process are incompletely understood. Here we report that the Trk Receptors are multimonoubiquitinated in response to neurotrophins. We have identified an E3 ubiquitin ligase, Nedd4-2, that associates with the TrkA Receptor and is phosphorylated upon NGF binding. The binding of Nedd4-2 to TrkA through a PPXY motif leads to the ubiquitination and downregulation of TrkA. Activated TrkA Receptor levels and the survival of NGF-dependent sensory neurons, but not BDNF-dependent sensory neurons, are directly influenced by Nedd4-2 expression. Unexpectedly, Nedd4-2 does not bind or ubiquitinate related TrkB Receptors, due to the lack of a consensus PPXY motif. Our results indicate that Trk neurotrophin Receptors are differentially regulated by ubiquitination to modulate the survival of neurons.
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A role for Fyn in Trk Receptor transactivation by G-protein-coupled Receptor signaling.
Molecular and Cellular Neuroscience, 2006Co-Authors: Rithwick Rajagopal, Moses V ChaoAbstract:Signaling through Trk Receptor tyrosine kinases can occur in the absence of neurotrophins through certain G-protein-coupled Receptors (GPCRs). It has previously been suggested that GPCR-mediated Trk activation occurs on intracellular membranes and involves several second messengers, including Src family kinases and intracellular calcium. Here, we describe a novel role for the Src family kinase, Fyn, in regulating signaling events between GPCRs and Trk. We find that Fyn expression is sufficient to allow transactivation of Trk by adenosine and that Fyn and Trk are colocalized in a juxtanuclear membrane compartment. Adenosine activation of Fyn results in direct phosphorylation of Trk in vitro and follows a delayed time course that coincides with Trk activation. These results indicate that Fyn is activated by GPCR stimulation and is responsible for transactivation of Trk Receptors on intracellular membranes.
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transactivation of Trk neurotrophin Receptors by g protein coupled Receptor ligands occurs on intracellular membranes
The Journal of Neuroscience, 2004Co-Authors: Rithwick Rajagopal, Zheyu Chen, Moses V ChaoAbstract:Neurotrophins, such as NGF and BDNF, activate Trk Receptor tyrosine kinases through Receptor dimerization at the cell surface followed by autophosphorylation and intracellular signaling. It has been shown that activation of Trk Receptor tyrosine kinases can also occur via a G-protein-coupled Receptor (GPCR) mechanism, without involvement of neurotrophins. Two GPCR ligands, adenosine and pituitary adenylate cyclase-activating polypeptide (PACAP), can activate Trk Receptor activity to increase the survival of neural cells through stimulation of Akt activity. To investigate the mechanism of Trk Receptor transactivation, we have examined the localization of Trk Receptors in PC12 cells and primary neurons after treatment with adenosine agonists and PACAP. In contrast to neurotrophin treatment, Trk Receptors were sensitive to transcriptional and translational inhibitors, and they were found predominantly in intracellular locations particularly associated with Golgi membranes. Biotinylation and immunostaining experiments confirm that most of the transactivated Trk Receptors are found in intracellular membranes. These results indicate that there are alternative modes of activating Trk Receptor tyrosine kinases in the absence of neurotrophin binding at the cell surface and that Receptor signaling may occur and persist inside of neuronal cells.
Susan O Meakin - One of the best experts on this subject based on the ideXlab platform.
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Trk Receptor binding and neurotrophin fibroblast growth factor fgf dependent activation of the fgf Receptor substrate frs 3
Biochimica et Biophysica Acta, 2006Co-Authors: Scott J Dixon, James I S Macdonald, Susan O Meakin, Kim N Robinson, Christopher J KubuAbstract:Abstract We have investigated the signaling properties of the fibroblast growth factor (FGF) Receptor substrate 3 (FRS3), also known as SNT-2 or FRS2β, in neurotrophin-dependent differentiation in comparison with the related adapter FRS2 (SNT1 or FRS2α). We demonstrate that FRS3 binds all neurotrophin Trk Receptor tyrosine kinases and becomes tyrosine phosphorylated in response to NGF, BDNF, NT-3 and FGF stimulation in transfected cells and/or primary cortical neurons. Second, the signaling molecules Grb2 and Shp2 bind FRS3 at consensus sites that are highly conserved among FRS family members and that Shp2, in turn, becomes tyrosine phosphorylated. While FRS3 over-expression in PC12 cells neither increases NGF-induced neuritogenesis nor activation of Map kinase/AKT, comparable to previous reports on FRS2, over-expression of a chimeric adapter containing the PH/PTB domains of the insulin Receptor substrate (IRS) 2, in place of the PTB domain of FRS3 (IRS2-FRS3) supports insulin-dependent Map kinase activation and neurite outgrowth in PC12 cells. Collectively, these data demonstrate that FRS3 supports ligand-induced Map kinase activation and that the chimeric IRS2-FRS3 adapter is stimulating sufficient levels of activated MapK to support neurite outgrowth in PC12 cells.
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Trk Receptor binding and neurotrophin fibroblast growth factor fgf dependent activation of the fgf Receptor substrate frs 3
Biochimica et Biophysica Acta, 2006Co-Authors: Scott J Dixon, James I S Macdonald, Susan O Meakin, Kim N Robinson, Christopher J KubuAbstract:We have investigated the signaling properties of the fibroblast growth factor (FGF) Receptor substrate 3 (FRS3), also known as SNT-2 or FRS2beta, in neurotrophin-dependent differentiation in comparison with the related adapter FRS2 (SNT1 or FRS2alpha). We demonstrate that FRS3 binds all neurotrophin Trk Receptor tyrosine kinases and becomes tyrosine phosphorylated in response to NGF, BDNF, NT-3 and FGF stimulation in transfected cells and/or primary cortical neurons. Second, the signaling molecules Grb2 and Shp2 bind FRS3 at consensus sites that are highly conserved among FRS family members and that Shp2, in turn, becomes tyrosine phosphorylated. While FRS3 over-expression in PC12 cells neither increases NGF-induced neuritogenesis nor activation of Map kinase/AKT, comparable to previous reports on FRS2, over-expression of a chimeric adapter containing the PH/PTB domains of the insulin Receptor substrate (IRS) 2, in place of the PTB domain of FRS3 (IRS2-FRS3) supports insulin-dependent Map kinase activation and neurite outgrowth in PC12 cells. Collectively, these data demonstrate that FRS3 supports ligand-induced Map kinase activation and that the chimeric IRS2-FRS3 adapter is stimulating sufficient levels of activated MapK to support neurite outgrowth in PC12 cells.
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Trk Receptor binding and neurotrophin/fibroblast growth factor (FGF)-dependent activation of the FGF Receptor substrate (FRS)-3
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2006Co-Authors: Scott J Dixon, James I S Macdonald, Kim N Robinson, Christopher J Kubu, Susan O MeakinAbstract:We have investigated the signaling properties of the fibroblast growth factor (FGF) Receptor substrate 3 (FRS3), also known as SNT-2 or FRS2beta, in neurotrophin-dependent differentiation in comparison with the related adapter FRS2 (SNT1 or FRS2alpha). We demonstrate that FRS3 binds all neurotrophin Trk Receptor tyrosine kinases and becomes tyrosine phosphorylated in response to NGF, BDNF, NT-3 and FGF stimulation in transfected cells and/or primary cortical neurons. Second, the signaling molecules Grb2 and Shp2 bind FRS3 at consensus sites that are highly conserved among FRS family members and that Shp2, in turn, becomes tyrosine phosphorylated. While FRS3 over-expression in PC12 cells neither increases NGF-induced neuritogenesis nor activation of Map kinase/AKT, comparable to previous reports on FRS2, over-expression of a chimeric adapter containing the PH/PTB domains of the insulin Receptor substrate (IRS) 2, in place of the PTB domain of FRS3 (IRS2-FRS3) supports insulin-dependent Map kinase activation and neurite outgrowth in PC12 cells. Collectively, these data demonstrate that FRS3 supports ligand-induced Map kinase activation and that the chimeric IRS2-FRS3 adapter is stimulating sufficient levels of activated MapK to support neurite outgrowth in PC12 cells.
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human tumorous imaginal disc 1 tid1 associates with Trk Receptor tyrosine kinases and regulates neurite outgrowth in nnr5 Trka cells
Journal of Biological Chemistry, 2005Co-Authors: Huiyu Liu, James I S Macdonald, Todd Hryciw, Susan O MeakinAbstract:Abstract The human tumorous imaginal disc 1 (TID1) proteins including TID1L and TID1S, members of the DnaJ domain protein family, are involved in multiple intracellular signaling pathways such as apoptosis induction, cell proliferation, and survival. Here we report that TID1 associates with the Trk Receptor tyrosine kinases and regulates nerve growth factor (NGF)-induced neurite outgrowth in PC12-derived nnr5 cells. Binding assays and transfection studies showed that the carboxyl-terminal end of TID1 (residues 224–429) bound to Trk at the activation loop (Tyr(P)683-Tyr684(P)684 in rat TrkA) and that TID1 was tyrosine phosphorylated by Trk both in yeast and in transfected cells. Moreover endogenous TID1 was also tyrosine phosphorylated by and co-immunoprecipitated with Trk in neurotrophin-stimulated primary rat hippocampal neurons. Overexpression studies showed that both TID1L and TID1S significantly facilitated NGF-induced neurite outgrowth in TrkA-expressing nnr5 cells possibly through a mechanism involving increased activation of mitogen-activated protein kinase. Consistently knockdown of endogenous TID1, mediated with specific short hairpin RNA, significantly reduced NGF-induced neurite growth in nnr5-TrkA cells. These data provide the first evidence that TID1 is a novel intracellular adaptor that interacts with the Trk Receptor tyrosine kinases in an activity-dependent manner to facilitate Trk-dependent intracellular signaling.
José Aguilera - One of the best experts on this subject based on the ideXlab platform.
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Trk Receptors need neutral sphingomyelinase activity to promote cell viability
FEBS Letters, 2013Co-Authors: Ana Candalija, Roger Cubí, Arturo Ortega, José Aguilera, Carles GilAbstract:Neurotrophins are a group of secreted polypeptides, which comprises Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF). Each neurotrophin can bind specifically to a tyrosine kinase Trk Receptor (TrkA, TrkB or TrkC), while all of the neurotrophins can bind, with similar affinity, to the p75 neurotrophin Receptor (p75NTR). Experiments on cell viability promotion by BDNF in granule neurons or by NGF in PC12 cells show that neurotrophin-exerted cell viability is neutral sphingomyelinase (nSMase)-dependent, since GW4869 or siRNA knockdown abrogates the protective effects, as well as neurotrophin-induced Akt phosphorylation. Finally, the assessment of nSMase activity promotion drives to the conclusion that neurotrophins can promote cell viability through Trk Receptors in a manner depending on basal nSMase but not through SMase activity enhancement.
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C-terminal fragment of tetanus toxin heavy chain activates Akt and MEK/ERK signalling pathways in a Trk Receptor-dependent manner in cultured cortical neurons.
The Biochemical journal, 2003Co-Authors: Carles Gil, Imane Chaib-oukadour, José AguileraAbstract:Previous publications from our group [Gil, Chaib, Pelliccioni and Aguilera (2000) FEBS Lett. 481, 177-182; Gil, Chaib, Blasi and Aguilera (2001) Biochem. J. 356, 97-103] have reported the activation, in rat brain synaptosomes, of several phosphoproteins, such as neurotrophin tyrosine kinase (Trk) A Receptor, phospholipase Cgamma-1, protein kinase C (PKC) isoforms and extracellular-signal-regulated kinases 1 and 2 (ERK-1/2). In the present study, we examined, by means of phospho-specific antibodies, the activation of the signalling cascades involving neurotrophin Trk Receptor, Akt kinase and ERK pathway, in cultured cortical neurons from foetal rat brain, by tetanus toxin (TeTx) as well as by the C-terminal part of its heavy chain (H(C)-TeTx). TeTx and H(C)-TeTx induce fast and transient phosphorylation of Trk Receptor at Tyr(674) and Tyr(675), but not at Tyr(490), although the potency of TeTx in this action was higher when compared with H(C)-TeTx action. Moreover, H(C)-TeTx and TeTx also induced phosphorylation of Akt (at Ser(473) and Thr(308)) and of ERK-1/2 (Thr(202)/Tyr(204)), in a time- and concentration-dependent manner. The detection of TeTx- and H(C)-TeTx-induced phosphorylation at Ser(9) of glycogen synthase kinase 3beta confirms Akt activation. In the extended analysis of the ERK pathway, phosphorylation of the Raf, mitogen-activated protein kinase kinase (MEK)-1/2 and p90Rsk kinases and phosphorylation of the transcription factor cAMP-response-element-binding protein were detected. The use of tyrphostin AG879, an inhibitor of Trk Receptors, demonstrates their necessary participation in the H(C)-TeTx-induced activation of Akt and ERK pathways, as well as in the phosphorylation of phospholipase Cgamma-1. Furthermore, both pathways are totally dependent on phosphatidylinositol 3-kinase action, and they are independent of PKC action, as assessed using wortmannin and Ro-31-8220 as inhibitors. The activation of PKC isoforms was determined by their translocation from the cytosolic compartment to the membranous compartment, showing a clear H(C)-TeTx-induced translocation of PKC-alpha and -beta, but not of PKC- epsilon.
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c terminal fragment of tetanus toxin heavy chain activates akt and mek erk signalling pathways in a Trk Receptor dependent manner in cultured cortical neurons
Biochemical Journal, 2003Co-Authors: Carles Gil, Imane Chaiboukadour, José AguileraAbstract:Previous publications from our group [Gil, Chaib, Pelliccioni and Aguilera (2000) FEBS Lett. 481, 177-182; Gil, Chaib, Blasi and Aguilera (2001) Biochem. J. 356, 97-103] have reported the activation, in rat brain synaptosomes, of several phosphoproteins, such as neurotrophin tyrosine kinase (Trk) A Receptor, phospholipase Cgamma-1, protein kinase C (PKC) isoforms and extracellular-signal-regulated kinases 1 and 2 (ERK-1/2). In the present study, we examined, by means of phospho-specific antibodies, the activation of the signalling cascades involving neurotrophin Trk Receptor, Akt kinase and ERK pathway, in cultured cortical neurons from foetal rat brain, by tetanus toxin (TeTx) as well as by the C-terminal part of its heavy chain (H(C)-TeTx). TeTx and H(C)-TeTx induce fast and transient phosphorylation of Trk Receptor at Tyr(674) and Tyr(675), but not at Tyr(490), although the potency of TeTx in this action was higher when compared with H(C)-TeTx action. Moreover, H(C)-TeTx and TeTx also induced phosphorylation of Akt (at Ser(473) and Thr(308)) and of ERK-1/2 (Thr(202)/Tyr(204)), in a time- and concentration-dependent manner. The detection of TeTx- and H(C)-TeTx-induced phosphorylation at Ser(9) of glycogen synthase kinase 3beta confirms Akt activation. In the extended analysis of the ERK pathway, phosphorylation of the Raf, mitogen-activated protein kinase kinase (MEK)-1/2 and p90Rsk kinases and phosphorylation of the transcription factor cAMP-response-element-binding protein were detected. The use of tyrphostin AG879, an inhibitor of Trk Receptors, demonstrates their necessary participation in the H(C)-TeTx-induced activation of Akt and ERK pathways, as well as in the phosphorylation of phospholipase Cgamma-1. Furthermore, both pathways are totally dependent on phosphatidylinositol 3-kinase action, and they are independent of PKC action, as assessed using wortmannin and Ro-31-8220 as inhibitors. The activation of PKC isoforms was determined by their translocation from the cytosolic compartment to the membranous compartment, showing a clear H(C)-TeTx-induced translocation of PKC-alpha and -beta, but not of PKC- epsilon.
Louis F Reichardt - One of the best experts on this subject based on the ideXlab platform.
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Trk Receptors: roles in neuronal signal transduction.
Annual Review of Biochemistry, 2003Co-Authors: Eric J Huang, Louis F ReichardtAbstract:Trk Receptors are a family of three Receptor tyrosine kinases, each of which can be activated by one or more of four neurotrophins-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophins 3 and 4 (NT3 and NT4). Neurotrophin signaling through these Receptors regulates cell survival, proliferation, the fate of neural precursors, axon and dendrite growth and patterning, and the expression and activity of functionally important proteins, such as ion channels and neurotransmitter Receptors. In the adult nervous system, the Trk Receptors regulate synaptic strength and plasticity. The cytoplasmic domains of Trk Receptors contain several sites of tyrosine phosphorylation that recruit intermediates in intracellular signaling cascades. As a result, Trk Receptor signaling activates several small G proteins, including Ras, Rap-1, and the Cdc-42-Rac-Rho family, as well as pathways regulated by MAP kinase, PI 3-kinase and phospholipase-C-gamma (PLC-gamma). Trk Receptor activation has different consequences in different cells, and the specificity of downstream Trk Receptor-mediated signaling is controlled through expression of intermediates in these signaling pathways and membrane trafficking that regulates localization of different signaling constituents. Perhaps the most fascinating aspect of Trk Receptor-mediated signaling is its interplay with signaling promoted by the pan-neurotrophin Receptor p75NTR. p75NTR activates a distinct set of signaling pathways within cells that are in some instances synergistic and in other instances antagonistic to those activated by Trk Receptors. Several of these are proapoptotic but are suppressed by Trk Receptor-initiated signaling. p75NTR also influences the conformations of Trk Receptors; this modifies ligand-binding specificity and affinity with important developmental consequences.
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Trk Receptors mediators of neurotrophin action
Current Opinion in Neurobiology, 2001Co-Authors: Ardem Patapoutian, Louis F ReichardtAbstract:Abstract The four mammalian neurotrophins — NGF, BDNF, NT-3 and NT-4 — each bind and activate one or more of the Trk family of Receptor tyrosine kinases. Through these Receptors, neurotrophins activate many intracellular signaling pathways, including those controlled by Ras, the Cdc42/Rac/RhoG protein family, MAPK, PI3K and PLC-γ, thereby affecting both development and function of the nervous system. During the past two years, several novel signaling pathways controlled by Trk Receptors have been characterized, and it has become clear that membrane transport and sorting controls Trk-Receptor-mediated signaling because key intermediates are localized to different membrane compartments. Three-dimensional structures of the Trk Receptors, in one instance in association with a neurotrophin, have revealed the structural bases underlying specificity in neurotrophin signaling.
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pou domain factor brn 3a controls the differentiation and survival of trigeminal neurons by regulating Trk Receptor expression
Development, 1999Co-Authors: Eric J Huang, Keling Zang, Andrea Schmidt, Asta Saulys, Mengqing Xiang, Louis F ReichardtAbstract:Mice lacking the POU domain-containing transcription factor Brn-3a have several neuronal deficits. In the present paper, we show that Brn-3a plays two distinct roles during development of the trigeminal ganglion. In this ganglion, neurons expressing the neurotrophin Receptors, TrkB and TrkC, are born between E9.5 and E11.5. In the absence of Brn-3a, very few neurons ever express TrkC, but TrkB-expressing neurons are present at E12.5 in elevated numbers, suggesting that Brn-3a may be a constituent of a regulatory circuit determining which Trk Receptor is expressed by these early-born neurons. Most neurons expressing the neurotrophin Receptor TrkA are generated between E11.5 and E13.5 in this ganglion and their initial generation is not prevented by absence of Brn-3a. However, after E12. 5, absence of Brn-3a results in a progressive loss in neuronal TrkA and TrkB expression, which leads to a massive wave of apoptosis that peaks at E15.5. Despite complete absence of the Trk Receptors at E17. 5 and P0, approximately 30% of the normal complement of neurons survive to birth in Brn-3a mutants. Approximately 70% of these express the GDNF Receptor subunit, c-ret; many can be sustained by GDNF, but not by NGF in culture. Thus, the vast majority of surviving neurons are probably sustained in vivo by trophic factor(s) whose Receptors are not regulated by Brn-3a. In conclusion, our data indicate the specific functions of Brn-3a in controlling the survival and differentiation of trigeminal neurons by regulating expression of each of the three Trk Receptors.
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EXPRESSION OF Trk ReceptorS IN THE DEVELOPING MOUSE TRIGEMINAL GANGLION : IN VIVO EVIDENCE FOR NT-3 ACTIVATION OF TrkA AND TrkB IN ADDITION TO TrkC
Development (Cambridge England), 1999Co-Authors: Eric J Huang, Isabel Farinas, George A Wilkinson, Carey Backus, Keling Zang, Sharyl L. Wong, Louis F ReichardtAbstract:Animals lacking neurotrophin-3 (NT-3) are born with deficits in almost all sensory ganglia. Among these, the trigeminal ganglion is missing 70% of the normal number of neurons, a deficit which develops during the major period of neurogenesis between embryonic stages (E) 10.5 and E13.5. In order to identify the mechanisms for this deficit, we used antisera specific for TrkA, TrkB, and TrkC to characterize and compare the expression patterns of each Trk Receptor in trigeminal ganglia of wild type and NT-3 mutants between E10.5 and E15.5. Strikingly, TrkA, TrkB, and TrkC proteins appear to be exclusively associated with neurons, not precursors. While some neurons show limited co-expression of Trk Receptors at E11.5, by E13. 5 each neuron expresses only one Trk Receptor. Neuronal birth dating and cell counts show that in wild-type animals all TrkB- and TrkC-expressing neurons are generated before E11.5, while the majority of TrkA-expressing neurons are generated between E11.5 and E13.5. In mice lacking NT-3, the initial formation of the ganglion, as assessed at E10.5, is similar to that in wild-type animals. At E11.5, however, the number of TrkC-expressing neurons is dramatically reduced and the number of TrkC-immunopositive apoptotic profiles is markedly elevated. By E13.5, TrkC-expressing neurons are virtually eliminated. At E11.5, compared to wild type, the number of TrkB-expressing neurons is also reduced and the number of TrkB immunoreactive apoptotic profiles is increased. TrkA neurons are also reduced in the NT-3 mutants, but the major deficit develops between E12.5 and E13.5 when elevated numbers of TrkA-immunoreactive apoptotic profiles are detected. Normal numbers of TrkA- and TrkB-expressing neurons are seen in a TrkC-deficient mutant. Therefore, our data provide evidence that NT-3 supports the survival of TrkA-, TrkB- and TrkC-expressing neurons in the trigeminal ganglion by activating directly each of these Receptors in vivo.
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characterization of neurotrophin and Trk Receptor functions in developing sensory ganglia direct nt 3 activation of Trkb neurons in vivo
Neuron, 1998Co-Authors: Isabel Farinas, George A Wilkinson, Carey Backus, Louis F Reichardt, Ardem PatapoutianAbstract:Spinal sensory ganglia have been shown to contain neuronal subpopulations with different functions and neurotrophin dependencies. Neurotrophins act, in large part, through Trk Receptor tyrosine kinases: nerve growth factor (NGF) via TrkA, brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5) via TrkB, and neurotrophin-3 (NT-3) via TrkC. In the present paper, we use antibodies to TrkA, TrkB, and TrkC to characterize their expression patterns and to determine which subpopulations of cells are lost in mice lacking individual neurotrophins or Trk Receptors. Despite previous reports of Trk Receptor mRNAs in neural crest cells, we detect Trk Receptor proteins only in neurons and not in neural crest cells or neuronal precursors. Comparisons of neonatal mice deficient in NT-3 or its cognate Receptor TrkC have shown that there is a much greater deficiency in spinal sensory neurons in the former, suggesting that NT-3 may activate Receptors in addition to TrkC. Using the same antibodies, we show that, during the major period of neurogenesis, NT-3 is required to maintain neurons that express TrkB in addition to those that express TrkC but is not essential for neurons expressing TrkA. Results also indicate that survival of cells expressing both Receptors can be maintained by activation of either one alone. NT-3 can thus activate more than one Trk Receptor in vivo, which when coexpressed are functionally redundant.
Carles Gil - One of the best experts on this subject based on the ideXlab platform.
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Trk Receptors need neutral sphingomyelinase activity to promote cell viability
FEBS Letters, 2013Co-Authors: Ana Candalija, Roger Cubí, Arturo Ortega, José Aguilera, Carles GilAbstract:Neurotrophins are a group of secreted polypeptides, which comprises Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF). Each neurotrophin can bind specifically to a tyrosine kinase Trk Receptor (TrkA, TrkB or TrkC), while all of the neurotrophins can bind, with similar affinity, to the p75 neurotrophin Receptor (p75NTR). Experiments on cell viability promotion by BDNF in granule neurons or by NGF in PC12 cells show that neurotrophin-exerted cell viability is neutral sphingomyelinase (nSMase)-dependent, since GW4869 or siRNA knockdown abrogates the protective effects, as well as neurotrophin-induced Akt phosphorylation. Finally, the assessment of nSMase activity promotion drives to the conclusion that neurotrophins can promote cell viability through Trk Receptors in a manner depending on basal nSMase but not through SMase activity enhancement.
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C-terminal fragment of tetanus toxin heavy chain activates Akt and MEK/ERK signalling pathways in a Trk Receptor-dependent manner in cultured cortical neurons.
The Biochemical journal, 2003Co-Authors: Carles Gil, Imane Chaib-oukadour, José AguileraAbstract:Previous publications from our group [Gil, Chaib, Pelliccioni and Aguilera (2000) FEBS Lett. 481, 177-182; Gil, Chaib, Blasi and Aguilera (2001) Biochem. J. 356, 97-103] have reported the activation, in rat brain synaptosomes, of several phosphoproteins, such as neurotrophin tyrosine kinase (Trk) A Receptor, phospholipase Cgamma-1, protein kinase C (PKC) isoforms and extracellular-signal-regulated kinases 1 and 2 (ERK-1/2). In the present study, we examined, by means of phospho-specific antibodies, the activation of the signalling cascades involving neurotrophin Trk Receptor, Akt kinase and ERK pathway, in cultured cortical neurons from foetal rat brain, by tetanus toxin (TeTx) as well as by the C-terminal part of its heavy chain (H(C)-TeTx). TeTx and H(C)-TeTx induce fast and transient phosphorylation of Trk Receptor at Tyr(674) and Tyr(675), but not at Tyr(490), although the potency of TeTx in this action was higher when compared with H(C)-TeTx action. Moreover, H(C)-TeTx and TeTx also induced phosphorylation of Akt (at Ser(473) and Thr(308)) and of ERK-1/2 (Thr(202)/Tyr(204)), in a time- and concentration-dependent manner. The detection of TeTx- and H(C)-TeTx-induced phosphorylation at Ser(9) of glycogen synthase kinase 3beta confirms Akt activation. In the extended analysis of the ERK pathway, phosphorylation of the Raf, mitogen-activated protein kinase kinase (MEK)-1/2 and p90Rsk kinases and phosphorylation of the transcription factor cAMP-response-element-binding protein were detected. The use of tyrphostin AG879, an inhibitor of Trk Receptors, demonstrates their necessary participation in the H(C)-TeTx-induced activation of Akt and ERK pathways, as well as in the phosphorylation of phospholipase Cgamma-1. Furthermore, both pathways are totally dependent on phosphatidylinositol 3-kinase action, and they are independent of PKC action, as assessed using wortmannin and Ro-31-8220 as inhibitors. The activation of PKC isoforms was determined by their translocation from the cytosolic compartment to the membranous compartment, showing a clear H(C)-TeTx-induced translocation of PKC-alpha and -beta, but not of PKC- epsilon.
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c terminal fragment of tetanus toxin heavy chain activates akt and mek erk signalling pathways in a Trk Receptor dependent manner in cultured cortical neurons
Biochemical Journal, 2003Co-Authors: Carles Gil, Imane Chaiboukadour, José AguileraAbstract:Previous publications from our group [Gil, Chaib, Pelliccioni and Aguilera (2000) FEBS Lett. 481, 177-182; Gil, Chaib, Blasi and Aguilera (2001) Biochem. J. 356, 97-103] have reported the activation, in rat brain synaptosomes, of several phosphoproteins, such as neurotrophin tyrosine kinase (Trk) A Receptor, phospholipase Cgamma-1, protein kinase C (PKC) isoforms and extracellular-signal-regulated kinases 1 and 2 (ERK-1/2). In the present study, we examined, by means of phospho-specific antibodies, the activation of the signalling cascades involving neurotrophin Trk Receptor, Akt kinase and ERK pathway, in cultured cortical neurons from foetal rat brain, by tetanus toxin (TeTx) as well as by the C-terminal part of its heavy chain (H(C)-TeTx). TeTx and H(C)-TeTx induce fast and transient phosphorylation of Trk Receptor at Tyr(674) and Tyr(675), but not at Tyr(490), although the potency of TeTx in this action was higher when compared with H(C)-TeTx action. Moreover, H(C)-TeTx and TeTx also induced phosphorylation of Akt (at Ser(473) and Thr(308)) and of ERK-1/2 (Thr(202)/Tyr(204)), in a time- and concentration-dependent manner. The detection of TeTx- and H(C)-TeTx-induced phosphorylation at Ser(9) of glycogen synthase kinase 3beta confirms Akt activation. In the extended analysis of the ERK pathway, phosphorylation of the Raf, mitogen-activated protein kinase kinase (MEK)-1/2 and p90Rsk kinases and phosphorylation of the transcription factor cAMP-response-element-binding protein were detected. The use of tyrphostin AG879, an inhibitor of Trk Receptors, demonstrates their necessary participation in the H(C)-TeTx-induced activation of Akt and ERK pathways, as well as in the phosphorylation of phospholipase Cgamma-1. Furthermore, both pathways are totally dependent on phosphatidylinositol 3-kinase action, and they are independent of PKC action, as assessed using wortmannin and Ro-31-8220 as inhibitors. The activation of PKC isoforms was determined by their translocation from the cytosolic compartment to the membranous compartment, showing a clear H(C)-TeTx-induced translocation of PKC-alpha and -beta, but not of PKC- epsilon.
