Publication: A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways.
dc.contributor.author | Pattwell, Siobhan S | |
dc.contributor.author | Arora, Sonali | |
dc.contributor.author | Cimino, Patrick J | |
dc.contributor.author | Ozawa, Tatsuya | |
dc.contributor.author | Szulzewsky, Frank | |
dc.contributor.author | Hoellerbauer, Pia | |
dc.contributor.author | Bonifert, Tobias | |
dc.contributor.author | Hoffstrom, Benjamin G | |
dc.contributor.author | Boiani, Norman E | |
dc.contributor.author | Bolouri, Hamid | |
dc.contributor.author | Correnti, Colin E | |
dc.contributor.author | Oldrini, Barbara | |
dc.contributor.author | Silber, John R | |
dc.contributor.author | Paddison, Patrick J | |
dc.contributor.author | Holland, Eric C | |
dc.contributor.author | Squatrito, Massimo | |
dc.contributor.funder | United States Department of Health and Human Services | |
dc.contributor.funder | American Cancer Society | |
dc.contributor.funder | French Development Agency | |
dc.contributor.funder | Alzheimer's Disease Research Center | |
dc.date.accessioned | 2021-03-09T15:47:29Z | |
dc.date.available | 2021-03-09T15:47:29Z | |
dc.date.issued | 2020-11-01 | |
dc.description.abstract | Independent scientific achievements have led to the discovery of aberrant splicing patterns in oncogenesis, while more recent advances have uncovered novel gene fusions involving neurotrophic tyrosine receptor kinases (NTRKs) in gliomas. The exploration of NTRK splice variants in normal and neoplastic brain provides an intersection of these two rapidly evolving fields. Tropomyosin receptor kinase B (TrkB), encoded NTRK2, is known for critical roles in neuronal survival, differentiation, molecular properties associated with memory, and exhibits intricate splicing patterns and post-translational modifications. Here, we show a role for a truncated NTRK2 splice variant, TrkB.T1, in human glioma. TrkB.T1 enhances PDGF-driven gliomas in vivo, augments PDGF-induced Akt and STAT3 signaling in vitro, while next generation sequencing broadly implicates TrkB.T1 in the PI3K signaling cascades in a ligand-independent fashion. These TrkB.T1 findings highlight the importance of expanding upon whole gene and gene fusion analyses to include splice variants in basic and translational neuro-oncology research. | es_ES |
dc.description.peerreviewed | SÃ | es_ES |
dc.description.sponsorship | We thank James Yan, Jenny Zhang, Deby Kumasaka, and Denis Adair for continued technical and administrative assistance and support throughout these experiments. Eero Castren at University of Helsinki provided pEF-BOS-TrkB plasmids used for RCAS-TrkB.T1 generation. We thank Francis S. Lee and Lino Tessarollo for providing breeding pairs of TrkB.T1-/- mice for antibody production. Luis Chiriboga at New York University School of Medicine provided helpful insight into histology protocols. We thank William A. Johnsen and Midori Clarke for assistance with antibody sequencing and protein purification. We thank the Tracy A. Goodpaster and Julie Randolph-Habecker at the Fred Hutchinson Experimental Histopathology Core for histology assistance during the antibody validation phase and Elizabeth Jensen at the Fred Hutchinson Genomics Core for help with all DNA sequencing. We thank Jeongwu Lee Do-Hyun Nam and Steven M. Pollard for providing cell isolates. Funding was provided by National Institutes of Health R01 CA195718 (E.C.H.), U54 CA193461 (E.C.H., F.S.), R01 CA100688 (E.C.H.), T32 CA965725 (S.S.P.), U54 DK106829 (S.S.P.), R21 CA223531 (S.S.P., E.C.H.), T32 CA080416 (P.H.), R01 CA190957 (P.J.P.; T.B.); Jacobs Foundation Research Fellowship (S.S.P.); American Cancer Society ACS-RSG-14-056-01 (P.J.P.); National Research Agency RTI2018-102035-B-I00 (M.S.); Seve Ballesteros Foundation (M.S.). Autopsy materials used in this study were obtained from the University of Washington Neuropathology Core, which is supported by the Alzheimer's Disease Research Center (AG05136), the Adult Changes in Thought Study (AG006781), and Morris K Udall Center of Excellence for Parkinson's Disease Research (NS062684) | es_ES |
dc.format.number | 1 | es_ES |
dc.format.page | 2977 | es_ES |
dc.format.volume | 11 | es_ES |
dc.identifier.citation | Nat Commun.2020;11(1):2977 | es_ES |
dc.identifier.doi | 10.1038/s41467-020-16786-5 | es_ES |
dc.identifier.e-issn | 2041-1723 | es_ES |
dc.identifier.journal | Nature communications | es_ES |
dc.identifier.pubmedID | 32532995 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/12179 | |
dc.language.iso | eng | es_ES |
dc.publisher | Nature Publishing Group | es_ES |
dc.relation.publisherversion | https://doi.org/10.1038/s41467-020-16786-5. | es_ES |
dc.repisalud.institucion | CNIO | es_ES |
dc.repisalud.orgCNIO | CNIO::Grupos de investigación::Grupo de Tumores Cerebrales Fundación Seve-Ballesteros | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.rights.license | Atribución-NoComercial-CompartirIgual 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | * |
dc.subject.mesh | RNA Splicing | es_ES |
dc.subject.mesh | Animals | es_ES |
dc.subject.mesh | Brain | es_ES |
dc.subject.mesh | Brain Neoplasms | es_ES |
dc.subject.mesh | Carcinogenesis | es_ES |
dc.subject.mesh | Cells, Cultured | es_ES |
dc.subject.mesh | Gene Expression Profiling | es_ES |
dc.subject.mesh | Gene Ontology | es_ES |
dc.subject.mesh | Glioma | es_ES |
dc.subject.mesh | High-Throughput Nucleotide Sequencing | es_ES |
dc.subject.mesh | Humans | es_ES |
dc.subject.mesh | Membrane Glycoproteins | es_ES |
dc.subject.mesh | Mice | es_ES |
dc.subject.mesh | NIH 3T3 Cells | es_ES |
dc.subject.mesh | Neural Stem Cells | es_ES |
dc.subject.mesh | Oncogene Proteins, Fusion | es_ES |
dc.subject.mesh | Oncogenes | es_ES |
dc.subject.mesh | Phosphatidylinositol 3-Kinases | es_ES |
dc.subject.mesh | RNA Isoforms | es_ES |
dc.subject.mesh | Receptor, trkB | es_ES |
dc.subject.mesh | Signal Transduction | es_ES |
dc.title | A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways. | es_ES |
dc.type | journal article | es_ES |
dc.type.hasVersion | VoR | es_ES |
dspace.entity.type | Publication | |
relation.isAuthorOfPublication | f21d0dbd-5174-4daf-8303-0c61db0abcb1 | |
relation.isAuthorOfPublication | 6dc4ed91-fcfd-4682-80c5-af24c6939404 | |
relation.isAuthorOfPublication.latestForDiscovery | f21d0dbd-5174-4daf-8303-0c61db0abcb1 |
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