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Mariano Barbacid - One of the best experts on this subject based on the ideXlab platform.
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trkc Neurotrophin 3 Receptor vertebrates ntrk3
The Protein Kinase FactsBook#R##N#Protein-Serine Kinases, 1995Co-Authors: Mariano BarbacidAbstract:The TrkC PTK is the high-affinity, signaling Receptor for Neurotrophin-3 (NT-3), a member of the NGF family of Neurotrophins. The TRKC locus encodes two classes of Receptor. One class that is designated TrkCTK+ are protein-tyrosine kinases. To date, four TrkCTK+ Receptor isoforms have been described. gpl45trkc/TrkC.Kl was originally cloned from a porcine brain cDNA library. The other three isoforms contain inserts of 14–39 amino acids. The sequences of the 14 and 25 residue inserts are unique, but the 39 residue insert present in TrkCK39 consists of the combined 25 and 14 amino acid inserts. The extracellular region of TrkC exhibits the same motifs as Trk and TrkB. The kinase domain of the Kl isoform is 76% and 83% identical to those of Trk and TrkB. The other TrkCTK+ tyrosine kinase isoforms have inserts in the middle of the kinase domain. The TrkCTK- isoforms are identical up to residue 528 and then have variable C-termini because of alternative splicing.
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disruption of the Neurotrophin 3 Receptor gene trkc eliminates la muscle afferents and results in abnormal movements
Nature, 1994Co-Authors: Rudiger Klein, Richard J Smeyne, Inmaculada Silossantiago, Sergio A Lira, Riccardo Brambilla, Sherri Bryant, Li Zhang, William D Snider, Mariano BarbacidAbstract:THE trkC gene1,2 is expressed throughout the mammalian nervous system3-5 and encodes a series of tyrosine protein kinase isoforms that serve as Receptors for Neurotrophin-3 (NT3), a member of the nerve growth factor (NGF) family of neurotrophic factors2,6–8. One of these isoforms, gp145trkC/TrkC Kl, mediates the trophic properties of NT3 in cultured cells2,6–8. Here we show that homozygous mice defective for TrkC tyrosine protein kinase Receptors lack la muscle afferent projections to spinal motor neurons and have fewer large myelinated axons in the dorsal root and posterior columns of the spinal cord. These mice display abnormal movements and postures, indicating that NT3/TrkC-dependent sensory neurons may play a primary role in proprioception, the sense of position and movement of the limbs.
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developmental expression of trkc the Neurotrophin 3 Receptor in the mammalian nervous system
The Journal of Neuroscience, 1994Co-Authors: Fabienne Lamballe, Richard J Smeyne, Mariano BarbacidAbstract:The mammalian trkC gene encodes a tyrosine protein kinase that serves as a functional Receptor for Neurotrophin-3 (NT-3). Here, we report that trkC is widely expressed in the developing and adult nervous system. Using in situ hybridization, we first detect trkC transcripts in the telencephalon and spinal cord of embryonic day 9.5 mouse embryos. In later embryonic development, trkC is expressed in various structures of the CNS including the caudatoputamen, septal nuclei, cerebellum, and brainstem. In the PNS, trkC hybridization appears to correlate, both temporally and spatially, with the outgrowth of axons toward their peripheral targets. trkC transcripts were also identified in the autonomous enteric nervous system as well as in some non-neural tissues such as the wall of the aorta and the acini of the submaxillary and sublingual glands. In the adult mouse, trkC gene expression is heterogeneously distributed throughout the brain, with highest levels in limbic and diencephalic structures. These results indicate that the trkC gene is widely expressed in the three identified branches of the mammalian nervous system and appears to correlate with the expression of NT-3, its cognate ligand. The apparent colocalization of trkC transcripts with NT-3 raises the possibility this Neurotrophin exerts its trophic effects by a paracrine and/or autocrine mechanism.
Mary E. Sutton - One of the best experts on this subject based on the ideXlab platform.
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activation of Neurotrophin 3 Receptor trkc induces apoptosis in medulloblastomas
Cancer Research, 1999Co-Authors: Mary E. Sutton, Diane J Lu, Liliana Goumnerova, Lyuda Goritchenko, Jill R Kaufman, Amy L Billet, Nancy J Tarbell, Julian Wu, Jeffrey C Allen, Charles D StilesAbstract:Elevated expression of the Neurotrophin-3 (NT-3) Receptor TrkC by childhood medulloblastomas is associated with favorable clinical outcome. Here, we provide evidence that TrkC is more than simply a passive marker of prognosis. We demonstrate that: (a) medulloblastomas undergo apoptosis in vitro when grown in the presence of NT-3; (b) overexpression of TrkC inhibits the growth of intracerebral xenografts of a medulloblastoma cell line in nude mice; and (c) trkC expression by individual tumor cells is highly correlated with apoptosis within primary medulloblastoma biopsy specimens. TrkC-mediated NT-3 signaling promotes apoptosis by activating multiple parallel signaling pathways and by inducing immediate-early gene expression of both c-jun and c-fos. Considered collectively, these results support the conclusion that the biological actions of TrkC activation affect medulloblastoma outcome by inhibiting tumor growth through the promotion of apoptosis.
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Neurotrophins in cerebellar granule cell development and medulloblastoma
Journal of Neuro-Oncology, 1997Co-Authors: Scott L. Pomeroy, Mary E. Sutton, Liliana C. Goumnerova, Rosalind A. SegalAbstract:Medulloblastomas may be derived from granule cells ofthe developing cerebellum. Children with tumors expressing highlevels of the Neurotrophin-3 Receptor, TrkC, have amore favorable outcome. During development, TrkC is expressedin the most mature granule cells. Favorable medulloblastomasmay be derived from more highly differentiated granulecells.
Rosalind A. Segal - One of the best experts on this subject based on the ideXlab platform.
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Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice.
Developmental Biology, 2003Co-Authors: Aaron L. Nelson, Rosalind A. Segal, Liliana Goumnerova, Sibel A. Algon, Ondrea Graves, Lisa Marie Sturla, David H. Rowitch, Scott L. PomeroyAbstract:Abstract Medulloblastoma is a cerebellar tumor that can arise through aberrant activation of Sonic hedgehog (Shh) signaling, which normally regulates cerebellar granule cell proliferation. Mutations of the Shh Receptor PATCHED (PTCH) are associated with medulloblastomas, which have not been found to have loss of PTCH heterozygosity. We address whether patched (Ptc) heterozygosity fundamentally alters granule cell differentiation and contributes to tumorigenesis by increasing proliferation and/or decreasing apoptosis in Ptc+/− mice. Our data show that postnatal Ptc+/− mouse granule cell precursor growth is not globally altered. However, many older Ptc+/− mice display abnormal cerebellar regions containing persistently proliferating granule cell precursors. Since fewer Ptc+/− mice form medulloblastomas, these granule cell rests represent a developmentally disrupted, but uncommitted stage of tumorigenesis. Although Ptc+/− mouse medulloblastomas express neurodevelopmental genes, they diverge from granule cell differentiation in their discordant coexpression of postmitotic markers despite their ongoing growth. Like human medulloblastomas, mouse tumors with reduced levels of the Neurotrophin-3 Receptor, trkC/Ntrk3, display decreased apoptosis in vivo, illustrating the role of TrkC in regulating tumor cell survival. These results indicate that Ptc heterozygosity contributes to tumorigenesis by predisposing a subset of granule cell precursors to the formation of proliferative rests and subsequent dysregulation of developmental gene expression.
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Neurotrophins in cerebellar granule cell development and medulloblastoma
Journal of Neuro-Oncology, 1997Co-Authors: Scott L. Pomeroy, Mary E. Sutton, Liliana C. Goumnerova, Rosalind A. SegalAbstract:Medulloblastomas may be derived from granule cells ofthe developing cerebellum. Children with tumors expressing highlevels of the Neurotrophin-3 Receptor, TrkC, have amore favorable outcome. During development, TrkC is expressedin the most mature granule cells. Favorable medulloblastomasmay be derived from more highly differentiated granulecells.
Poul H.b. Sorensen - One of the best experts on this subject based on the ideXlab platform.
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ETV6-NTRK3: a chimeric protein tyrosine kinase with transformation activity in multiple cell lineages.
Seminars in Cancer Biology, 2005Co-Authors: Chris L. Lannon, Poul H.b. SorensenAbstract:Abstract The ETV6–NTRK3 (TEL–TRKC) gene fusion was discovered by breakpoint analysis of the t(12;15)(p13;q25) translocation associated with congenital fibrosarcoma, a pediatric soft tissue malignancy. ETV6–NTRK3 (EN) encodes the sterile alpha motif oligomerization domain of the ETV6 (TEL) transcription factor linked to the protein tyrosine kinase domain of the Neurotrophin-3 Receptor NTRK3 (TRKC). The EN chimeric oncoprotein links to multiple signaling cascades including Ras-MAP kinase and PI3K-AKT through the IRS-1 adapter protein. Recent evidence indicates that a functional insulin-like growth factor 1 Receptor axis and higher order polymer formation are essential for EN oncogenesis. EN has been detected in other malignancies, including secretory breast carcinoma. This chimeric oncoprotein is therefore unique in being expressed in tumors derived from multiple cell lineages.
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The ETV6-NTRK3 gene fusion encodes a chimeric protein tyrosine kinase that transforms NIH3T3 cells.
Oncogene, 2000Co-Authors: Stevan R Knezevich, Trevor Lucas, Burkhard Jansen, Poul H.b. SorensenAbstract:The congenital fibrosarcoma t(12;15)(p13;q25) rearrangement splices the ETV6 (TEL) gene on chromosome 12p13 in frame with the NTRK3 (TRKC) Neurotrophin-3 Receptor gene on chromosome 15q25. Resultant ETV6NTRK3 fusion transcripts encode the helix‐loop‐helix (HLH) dimerization domain of ETV6 fused to the protein tyrosine kinase (PTK) domain of NTRK3. We show here that ETV6-NTRK3 homodimerizes and is capable of forming heterodimers with wild-type ETV6. Moreover, ETV6-NTRK3 has PTK activity and is autophosphorylated on tyrosine residues. To determine if the fusion protein has transforming activity, NIH3T3 cells were infected with recombinant retroviral vectors carrying the full-length ETV6-NTRK3 cDNA. These cells exhibited a transformed phenotype, grew macroscopic colonies in soft agar, and formed tumors in severe combined immunodeficient (SCID) mice. We hypothesize that chimeric proteins mediate transformation by dysregulating NTRK3 signal transduction pathways via ligand-independent dimerization and PTK activation. To test this hypothesis, we expressed a series of ETV6NTRK3 mutants in NIH3T3 cells and assessed their transformation activities. Deletion of the ETV6 HLH domain abolished dimer formation with either ETV6 or ETV6-NTRK3, and cells expressing this mutant protein were morphologically non-transformed and failed to grow in soft agar. An ATP-binding mutant failed to autophosphorylate and completely lacked transformation activity. Mutants of the three NTRK3 PTK activationloop tyrosines had variable PTK activity but had limited to absent transformation activity. Of a series of signaling molecules well known to bind to wild-type NTRK3, only phospholipase-Cg (PLCg) associated with ETV6NTRK3. However, a PTK active mutant unable to bind PLCg did not show defects in transformation activity. Our studies confirm that ETV6-NTRK3 is a transforming protein that requires both an intact dimerization domain and a functional PTK domain for transformation activity. Oncogene (2000) 19, 906‐915.
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The ETV6-NTRK3 gene fusion encodes a chimeric protein tyrosine kinase that transforms NIH3T3 cells
Oncogene, 2000Co-Authors: Stevan R Knezevich, Trevor Lucas, Burkhard Jansen, Poul H.b. SorensenAbstract:The congenital fibrosarcoma t(12;15)(p13;q25) rearrangement splices the ETV6 ( TEL ) gene on chromosome 12p13 in frame with the NTRK3 ( TRKC ) Neurotrophin-3 Receptor gene on chromosome 15q25. Resultant ETV6-NTRK3 fusion transcripts encode the helix–loop–helix (HLH) dimerization domain of ETV6 fused to the protein tyrosine kinase (PTK) domain of NTRK3. We show here that ETV6-NTRK3 homodimerizes and is capable of forming heterodimers with wild-type ETV6. Moreover, ETV6-NTRK3 has PTK activity and is autophosphorylated on tyrosine residues. To determine if the fusion protein has transforming activity, NIH3T3 cells were infected with recombinant retroviral vectors carrying the full-length ETV6-NTRK3 cDNA. These cells exhibited a transformed phenotype, grew macroscopic colonies in soft agar, and formed tumors in severe combined immunodeficient (SCID) mice. We hypothesize that chimeric proteins mediate transformation by dysregulating NTRK3 signal transduction pathways via ligand-independent dimerization and PTK activation. To test this hypothesis, we expressed a series of ETV6-NTRK3 mutants in NIH3T3 cells and assessed their transformation activities. Deletion of the ETV6 HLH domain abolished dimer formation with either ETV6 or ETV6-NTRK3, and cells expressing this mutant protein were morphologically non-transformed and failed to grow in soft agar. An ATP-binding mutant failed to autophosphorylate and completely lacked transformation activity. Mutants of the three NTRK3 PTK activation-loop tyrosines had variable PTK activity but had limited to absent transformation activity. Of a series of signaling molecules well known to bind to wild-type NTRK3, only phospholipase-Cγ (PLCγ) associated with ETV6-NTRK3. However, a PTK active mutant unable to bind PLCγ did not show defects in transformation activity. Our studies confirm that ETV6-NTRK3 is a transforming protein that requires both an intact dimerization domain and a functional PTK domain for transformation activity.
Scott L. Pomeroy - One of the best experts on this subject based on the ideXlab platform.
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A novel role for extracellular signal-regulated kinase 5 and myocyte enhancer factor 2 in medulloblastoma cell death.
Cancer Research, 2005Co-Authors: Lisa Marie Sturla, Christopher W. Cowan, Lillian M. Guenther, Robert C. Castellino, Scott L. PomeroyAbstract:Expression of the Neurotrophin-3 Receptor, tyrosine kinase C (TrkC), is associated with favorable prognosis in medulloblastoma patients. This may be due to increased tumor apoptosis induced by TrkC activation. Neurotrophin-3/TrkC–induced apoptosis is inhibited by the mitogen-activated protein (MAP) kinase (MAPK) pharmacologic antagonists SB203580 and PD98059. In addition to extracellular signal-regulated kinase (ERK)-1/2, PD98059 also inhibits the more recently identified Neurotrophin-responsive MAPK, ERK5 (big MAPK 1). In the present study, we investigate the contribution of ERK5 and its target myocyte enhancer factor 2 (MEF2) to Neurotrophin-3/TrkC–induced medulloblastoma cell death. Neurotrophin-3 not only enhanced ERK5 phosphorylation but also significantly enhanced the transcriptional activity of MEF2, a specific target of ERK5. Overexpression of both ERK5 and MEF2 induced a statistically significant increase in cell death of Neurotrophin-3–responsive and nonresponsive medulloblastoma cell lines (Daoy-trkC and Daoy) and primary cultures of patched heterozygous mouse medulloblastomas. Only those cells expressing MAP/ERK kinase 5 (MEK5) plus ERK5 or MEF2 constructs underwent apoptosis, indicating that overexpression of either is sufficient to induce medulloblastoma cell death. Expression of a dominant-negative MEF2 or small interfering RNA for the ERK5 activator, MEK5, significantly inhibited Neurotrophin-3–induced cell death. The dominant-negative MEF2 construct also blocked MEK5/ERK5-induced cell death, supporting a role for MEF2 downstream of ERK5. Coimmunoprecipitation studies revealed direct interaction of phosphorylated ERK5 with MEF2 in response to Neurotrophin-3. Our investigation of the mechanism of Neurotrophin-3/TrkC–induced apoptosis has identified a novel role for both MEK5/ERK5 and MEF2 in cell death, suggesting that these molecules can be exploited to induce apoptosis in both TrkC-expressing and nonexpressing medulloblastoma cells.
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Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice.
Developmental Biology, 2003Co-Authors: Aaron L. Nelson, Rosalind A. Segal, Liliana Goumnerova, Sibel A. Algon, Ondrea Graves, Lisa Marie Sturla, David H. Rowitch, Scott L. PomeroyAbstract:Abstract Medulloblastoma is a cerebellar tumor that can arise through aberrant activation of Sonic hedgehog (Shh) signaling, which normally regulates cerebellar granule cell proliferation. Mutations of the Shh Receptor PATCHED (PTCH) are associated with medulloblastomas, which have not been found to have loss of PTCH heterozygosity. We address whether patched (Ptc) heterozygosity fundamentally alters granule cell differentiation and contributes to tumorigenesis by increasing proliferation and/or decreasing apoptosis in Ptc+/− mice. Our data show that postnatal Ptc+/− mouse granule cell precursor growth is not globally altered. However, many older Ptc+/− mice display abnormal cerebellar regions containing persistently proliferating granule cell precursors. Since fewer Ptc+/− mice form medulloblastomas, these granule cell rests represent a developmentally disrupted, but uncommitted stage of tumorigenesis. Although Ptc+/− mouse medulloblastomas express neurodevelopmental genes, they diverge from granule cell differentiation in their discordant coexpression of postmitotic markers despite their ongoing growth. Like human medulloblastomas, mouse tumors with reduced levels of the Neurotrophin-3 Receptor, trkC/Ntrk3, display decreased apoptosis in vivo, illustrating the role of TrkC in regulating tumor cell survival. These results indicate that Ptc heterozygosity contributes to tumorigenesis by predisposing a subset of granule cell precursors to the formation of proliferative rests and subsequent dysregulation of developmental gene expression.
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Neurotrophins in cerebellar granule cell development and medulloblastoma
Journal of Neuro-Oncology, 1997Co-Authors: Scott L. Pomeroy, Mary E. Sutton, Liliana C. Goumnerova, Rosalind A. SegalAbstract:Medulloblastomas may be derived from granule cells ofthe developing cerebellum. Children with tumors expressing highlevels of the Neurotrophin-3 Receptor, TrkC, have amore favorable outcome. During development, TrkC is expressedin the most mature granule cells. Favorable medulloblastomasmay be derived from more highly differentiated granulecells.