Early BDNF, NT-3, and NT-4 Signaling Events

Much more is known about nerve growth factor (NGF) signaling than that initiated by brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or NT-4. We sought to study early BDNF, NT-3, and NT-4 signaling events. Using TrkB-expressing cells, we found that BDNF and NT-4 individually induced tyrosine phosphorylation of TrkB in a dose-dependent fashion. At maximally effective concentrations, BDNF or NT-4 induced robust TrkB tyrosine phosphorylation at 5 min; this progressively declined at 15, 30, and 60 min. Using immunoprecipitation, PI3-kinase and tyrosine phosphorylated PLC-gamma1 and SHC were shown to be associated with tyrosine phosphorylated TrkB in response to both BDNF and NT-4. BDNF and NT-4 induced similar intensities of phosphorylation of TrkB and signaling intermediates at equivalent doses. NT-3 treatment of TrkC-expressing cells induced very similar patterns for induction of TrkC tyrosine phosphorylation and recruitment of signaling intermediates. BDNF, NT-3, and NT-4 caused rapid tyrosine phosphorylation of ERK and SNT. These data suggest that the earliest signaling events for BDNF, NT-3, and NT-4 are very similar to those for NGF.

[1]  K. Unsicker,et al.  The neurotrophins BDNF, NT-3 and -4, but not NGF, TGF-β1 and GDNF, increase the number of NADPH-diaphorase-reactive neurons in rat spinal cord cultures , 1995, Neuroscience.

[2]  D. Kaplan,et al.  SNT, a differentiation-specific target of neurotrophic factor-induced tyrosine kinase activity in neurons and PC12 cells , 1993, Molecular and cellular biology.

[3]  A. Aguayo,et al.  Neurotrophin-4/5 (NT-4/5) increases adult rat retinal ganglion cell survival and neurite outgrowth in vitro. , 1994, Journal of neurobiology.

[4]  G. Lewin,et al.  Neurotrophins Live or Let Die: Does p75NTR Decide? , 1997, Neuron.

[5]  Nancy Y. Ip,et al.  ERKs: A family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF , 1991, Cell.

[6]  M. Mattson,et al.  Neurotrophin-4/5 protects hippocampal and cortical neurons against energy deprivation- and excitatory amino acid-induced injury , 1994, Brain Research.

[7]  R. Lindsay,et al.  The NeurotroDhins BDNF, NT‐3 and NT‐4/5 Promote Survival and Morphological and Biochemical Differentiation of Striatal Neurons In Vitro , 1995, The European journal of neuroscience.

[8]  G. Yancopoulos,et al.  Trkl3 mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor , 1991, Cell.

[9]  T. Hunter,et al.  The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor , 1991, Cell.

[10]  R. Vandlen,et al.  Neurotrophin-4/5 is a mammalian-specific survival factor for distinct populations of sensory neurons , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[11]  R. Lindsay,et al.  The Neurotrophins NT-4/5 and BDNF Augment Serotonin, Dopamine, and GABAergic Systems during Behaviorally Effective Infusions to the Substantia Nigra , 1994, Experimental Neurology.

[12]  Lewis C Cantley,et al.  PI3K: Downstream AKTion Blocks Apoptosis , 1997, Cell.

[13]  R R Stewart,et al.  Neurotrophin-4/5 enhances survival of cultured spiral ganglion neurons and protects them from cisplatin neurotoxicity , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  R. Lindsay,et al.  Overlapping and Additive Effects of Neurotrophins and CNTF on Cultured Human Spinal Cord Neurons , 1994, Experimental Neurology.

[15]  Y. Barde,et al.  A splice variant of the neurotrophin receptor trkB with increased specificity for brain‐derived neurotrophic factor. , 1996, The EMBO journal.

[16]  D. Kaplan,et al.  Neurotrophin-induced trk receptor phosphorylation and cholinergic neuron response in primary cultures of embryonic rat brain neurons. , 1992, Neuroreport.

[17]  D. Kaplan,et al.  Regulated neurotrophin receptor responsiveness during neuronal migrationand early differentiation , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[18]  A. Fischer,et al.  Binding of CD4 ligands induces tyrosine phosphorylation of phosphatidylinositol-3 kinase p110 subunit. , 1998, International immunology.

[19]  W. Mobley,et al.  Multiple Levels for Regulation of TrkA in PC12 Cells by Nerve Growth Factor , 1995, Journal of neurochemistry.

[20]  I. Kang,et al.  The regulatory mechanism of phosphatidylinositol 3-kinase by insulin in 3T3 L1 fibroblasts: phosphorylation-independent activation of phosphatidylinositol 3-kinase , 1998, Experimental & Molecular Medicine.

[21]  M. Bothwell,et al.  Functional interactions of neurotrophins and neurotrophin receptors. , 1995, Annual review of neuroscience.

[22]  A. Björklund,et al.  Reversal of spatial memory impairments in aged rats by nerve growth factor and neurotrophins 3 and 4/5 but not by brain-derived neurotrophic factor. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[23]  T. Hunter,et al.  Identification of TrkB autophosphorylation sites and evidence that phospholipase C-gamma 1 is a substrate of the TrkB receptor. , 1994, The Journal of biological chemistry.

[24]  F. Hefti,et al.  Neurotrophin‐4/5 Promotes Survival and Differentiation of Rat Striatal Neurons Developing in Culture , 1994, The European journal of neuroscience.

[25]  L. Cantley,et al.  Nerve growth factor promotes the activation of phosphatidylinositol 3-kinase and its association with the trk tyrosine kinase. , 1992, The Journal of biological chemistry.

[26]  G. Yancopoulos,et al.  Functional analysis of mutant neurotrophins deficient in low‐affinity binding reveals a role for p75LNGFR in NT‐4 signalling. , 1995, The EMBO journal.

[27]  G. Yancopoulos,et al.  Neurotrophin-4 is a target-derived neurotrophic factor for neurons of the trigeminal ganglion. , 1993, Development.

[28]  L. Greene,et al.  Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells , 1993, Neuron.

[29]  W. Hendrickson,et al.  Characterization and crystallization of recombinant human neurotrophin-4. , 1994, The Journal of biological chemistry.

[30]  C. Shatz,et al.  Inhibition of ocular dominance column formation by infusion of NT-4/5 or BDNF , 1995, Science.

[31]  J-L Zheng,et al.  Neurotrophin-4/5 (NT-4/5) and brain-derived neurotrophic factor (BDNF) act at later stages of cerebellar granule cell differentiation , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[32]  S. McMahon,et al.  Neurotrophins promote motor neuron survival and are present in embryonic limb bud , 1993, Nature.

[33]  D. Kaplan,et al.  Signal transduction by the neutrophin receptors , 1997 .

[34]  M. Barbacid,et al.  Signal transduction events mediated by the BDNF receptor gp 145trkB in primary hippocampal pyramidal cell culture , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[35]  R. Levi‐montalcini,et al.  The nerve growth factor 35 years later. , 1987, Science.

[36]  R. Oppenheim,et al.  Neurotrophic agents prevent motoneuron death following sciatic nerve section in the neonatal mouse. , 1994, Journal of neurobiology.

[37]  R. Lindsay.  8 – Brain-Derived Neurotrophic Factor: An NGF-Related Neurotrophin , 1993 .

[38]  W. Mobley,et al.  Expression of TrkA confers neuron-like responsiveness to nerve growth factor on an immortalized hypothalamic cell line. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[39]  M. Muda,et al.  Induction of the mitogen‐activated protein kinase phosphatase MKP3 by nerve growth factor in differentiating PC12 , 1998, FEBS letters.

[40]  Y. Yazaki,et al.  Formation of distinct signalling complexes involving phosphatidylinositol 3‐kinase activity with stimulation of epidermal growth factor or insulin‐like growth factor‐I in human skin fibroblasts , 1999, Journal of cellular physiology.

[41]  Y. Shimizu,et al.  A role for phosphatidylinositol 3-kinase in the regulation of beta 1 integrin activity by the CD2 antigen , 1995, The Journal of cell biology.

[42]  M. Barbacid,et al.  The trkB tyrosine protein kinase is a receptor for neurotrophin-4 , 1992, Neuron.

[43]  G. Yancopoulos,et al.  Naturally Occurring Tyrosine Kinase Inserts Block High Affinity Binding of Phospholipase Cγ and Shc to TrkC and Neurotrophin-3 Signaling (*) , 1995, The Journal of Biological Chemistry.

[44]  W. Mobley,et al.  Therapeutic potential of neurotrophic factors for neurological disorders , 1996, Annals of neurology.

[45]  R. Vejsada,et al.  Quantitative Comparison of the Transient Rescue Effects of Neurotrophic Factors on Axotomized Motoneurons In Vivo , 1995, The European journal of neuroscience.

[46]  Alan R. Saltiel,et al.  Activation of phosphatidylinositol-3 kinase by nerve growth factor involves indirect coupling of the trk proto-oncogene with src homology 2 domains , 1992, Neuron.

[47]  D. Price,et al.  Neurotrophin 4/5 is a trophic factor for mammalian facial motor neurons. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[48]  I. Black,et al.  Differential Actions of Neurotrophins in the Locus Coeruleus and Basal Forebrain , 1993, Experimental Neurology.

[49]  D. Kleinfeld,et al.  BDNF and NT-4/5 exert neurotrophic influences on injured adult spinal motor neurons , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[50]  M. Barbacid,et al.  trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3 , 1991, Cell.

[51]  F. Hefti,et al.  Stimulation of GABAergic neuron differentiation by NT-4/5 in cultures of rat cerebral cortex. , 1994, Brain research. Developmental brain research.

[52]  R. Lindsay,et al.  Characterization of the Responses of Purkinje Cells to Neurotrophin Treatment , 1996, Journal of neurochemistry.

[53]  R. Stewart,et al.  Neurotrophin-4/5, brain-derived neurotrophic factor, and neurotrophin-3 promote survival of cultured vestibular ganglion neurons and protect them against neurotoxicity of ototoxins. , 1995, Journal of neurobiology.

[54]  N. Ip,et al.  The Neurotrophins BDNF, NT‐3 and NT‐4/5, But Not NGF, Up‐regulate the Cholinergic Phenotype of Developing Motor Neurons , 1993, The European journal of neuroscience.

[55]  E. Van Obberghen,et al.  Regulation of extracellular signal-regulated protein kinase-1 (ERK-1; pp44/mitogen-activated protein kinase) by epidermal growth factor and nerve growth factor in PC12 cells: implication of ERK1 inhibitory activities. , 1993, Endocrinology.

[56]  R. Stephens,et al.  Neurotrophin signal transduction by the Trk receptor. , 1994, Journal of neurobiology.

[57]  H. Hatanaka,et al.  Brain-derived neurotrophic factor (BDNF) can prevent apoptosis of rat cerebellar granule neurons in culture. , 1995, Brain research. Developmental brain research.

[58]  C. Spenger,et al.  Comparison of the Effects of the Neurotrophins on the Morphological Structure of Dopaminergic Neurons in Cultures of Rat Substantia Nigra , 1995, The European journal of neuroscience.

[59]  K. Roth,et al.  Neurotrophin-4 selectively promotes survival of striatal neurons in organotypic slice culture , 1994, Brain Research.

[60]  B. Margolis,et al.  Phosphatidylinositol 3′‐kinase is activated by association with IRS‐1 during insulin stimulation. , 1992, The EMBO journal.

[61]  Y. Li,et al.  Cultured hippocampal neurons show responses to BDNF, NT-3, and NT-4, but not NGF , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.