NTRK1/TrkA Signaling in Neuroblastoma Cells Induces Nuclear Reorganization and Intra-Nuclear Aggregation of Lamin A/C

(1) Background: Neuroblastomas (NBs) are the most common extracranial solid tumors of children. The amplification of the Myc-N proto-oncogene (MYCN) is a major driver of NB aggressiveness, while high expression of the neurotrophin receptor NTRK1/TrkA is associated with mild disease courses. The mole...

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Autores principales: Lukas Funke, Thilo Bracht, Sebastian Oeck, Karin Schork, Markus Stepath, Sabine Dreesmann, Martin Eisenacher, Barbara Sitek, Alexander Schramm
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Publicado: MDPI AG 2021
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spelling oai:doaj.org-article:ccae7d8193394cd68660886cb97372272021-11-11T15:27:28ZNTRK1/TrkA Signaling in Neuroblastoma Cells Induces Nuclear Reorganization and Intra-Nuclear Aggregation of Lamin A/C10.3390/cancers132152932072-6694https://doaj.org/article/ccae7d8193394cd68660886cb97372272021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5293https://doaj.org/toc/2072-6694(1) Background: Neuroblastomas (NBs) are the most common extracranial solid tumors of children. The amplification of the Myc-N proto-oncogene (MYCN) is a major driver of NB aggressiveness, while high expression of the neurotrophin receptor NTRK1/TrkA is associated with mild disease courses. The molecular effects of NTRK1 signaling in MYCN-amplified NB, however, are still poorly understood and require elucidation. (2) Methods: Inducible NTRK1 expression was realized in four NB cell lines with (IMR5, NGP) or without MYCN amplification (SKNAS, SH-SY5Y). Proteome and phosphoproteome dynamics upon NTRK1 activation by its ligand, NGF, were analyzed in a time-dependent manner in IMR5 cells. Target validation by immunofluorescence staining and automated image processing was performed using the three other NB cell lines. (3) Results: In total, 230 proteins and 134 single phosphorylated class I phosphosites were found to be significantly regulated upon NTRK1 activation. Among known NTRK1 targets, Stathmin and the neurosecretory protein VGF were recovered. Additionally, we observed the upregulation and phosphorylation of Lamin A/C (LMNA) that accumulated inside nuclear foci. (4) Conclusions: We provide a comprehensive picture of NTRK1-induced proteome and phosphoproteome dynamics. The phosphorylation of LMNA within nucleic aggregates was identified as a prominent feature of NTRK1 signaling independent of the MYCN status of NB cells.Lukas FunkeThilo BrachtSebastian OeckKarin SchorkMarkus StepathSabine DreesmannMartin EisenacherBarbara SitekAlexander SchrammMDPI AGarticlephosphoproteomicsmass spectrometryphosphorylationproteomicsMYCNnuclear fociNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5293, p 5293 (2021)
institution DOAJ
collection DOAJ
language EN
topic phosphoproteomics
mass spectrometry
phosphorylation
proteomics
MYCN
nuclear foci
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
spellingShingle phosphoproteomics
mass spectrometry
phosphorylation
proteomics
MYCN
nuclear foci
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
Lukas Funke
Thilo Bracht
Sebastian Oeck
Karin Schork
Markus Stepath
Sabine Dreesmann
Martin Eisenacher
Barbara Sitek
Alexander Schramm
NTRK1/TrkA Signaling in Neuroblastoma Cells Induces Nuclear Reorganization and Intra-Nuclear Aggregation of Lamin A/C
description (1) Background: Neuroblastomas (NBs) are the most common extracranial solid tumors of children. The amplification of the Myc-N proto-oncogene (MYCN) is a major driver of NB aggressiveness, while high expression of the neurotrophin receptor NTRK1/TrkA is associated with mild disease courses. The molecular effects of NTRK1 signaling in MYCN-amplified NB, however, are still poorly understood and require elucidation. (2) Methods: Inducible NTRK1 expression was realized in four NB cell lines with (IMR5, NGP) or without MYCN amplification (SKNAS, SH-SY5Y). Proteome and phosphoproteome dynamics upon NTRK1 activation by its ligand, NGF, were analyzed in a time-dependent manner in IMR5 cells. Target validation by immunofluorescence staining and automated image processing was performed using the three other NB cell lines. (3) Results: In total, 230 proteins and 134 single phosphorylated class I phosphosites were found to be significantly regulated upon NTRK1 activation. Among known NTRK1 targets, Stathmin and the neurosecretory protein VGF were recovered. Additionally, we observed the upregulation and phosphorylation of Lamin A/C (LMNA) that accumulated inside nuclear foci. (4) Conclusions: We provide a comprehensive picture of NTRK1-induced proteome and phosphoproteome dynamics. The phosphorylation of LMNA within nucleic aggregates was identified as a prominent feature of NTRK1 signaling independent of the MYCN status of NB cells.
format article
author Lukas Funke
Thilo Bracht
Sebastian Oeck
Karin Schork
Markus Stepath
Sabine Dreesmann
Martin Eisenacher
Barbara Sitek
Alexander Schramm
author_facet Lukas Funke
Thilo Bracht
Sebastian Oeck
Karin Schork
Markus Stepath
Sabine Dreesmann
Martin Eisenacher
Barbara Sitek
Alexander Schramm
author_sort Lukas Funke
title NTRK1/TrkA Signaling in Neuroblastoma Cells Induces Nuclear Reorganization and Intra-Nuclear Aggregation of Lamin A/C
title_short NTRK1/TrkA Signaling in Neuroblastoma Cells Induces Nuclear Reorganization and Intra-Nuclear Aggregation of Lamin A/C
title_full NTRK1/TrkA Signaling in Neuroblastoma Cells Induces Nuclear Reorganization and Intra-Nuclear Aggregation of Lamin A/C
title_fullStr NTRK1/TrkA Signaling in Neuroblastoma Cells Induces Nuclear Reorganization and Intra-Nuclear Aggregation of Lamin A/C
title_full_unstemmed NTRK1/TrkA Signaling in Neuroblastoma Cells Induces Nuclear Reorganization and Intra-Nuclear Aggregation of Lamin A/C
title_sort ntrk1/trka signaling in neuroblastoma cells induces nuclear reorganization and intra-nuclear aggregation of lamin a/c
publisher MDPI AG
publishDate 2021
url https://doaj.org/article/ccae7d8193394cd68660886cb9737227
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