The alternative TrkAIII splice variant targets the centrosome and promotes genetic instability (459 views)
Mol Cell Biol (ISSN: 1098-5549, 0270-7306), 2009 Sep 1; 29(17): 4812-4830.
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Paper type: Journal Article, Research Support, Non-U. S. Gov'T,
Impact factor: 6.057, 5-year impact factor: 6.367
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-68849121025&partnerID=40&md5=c44b0a54ee181c26e4365897ef9b6d56
Keywords: Cell Cycle Protein 37, Endoplasmic Reticulum Golgi Intermediate Compartment Protein, Gamma Tubulin, Geldanamycin, Heat Shock Protein 90, Lectin, Polo Like Kinase, Protein Tyrosine Kinase A, Protein Tyrosine Phosphatase, Separase, Unclassified Drug, Anaphase, Animal Cell, Article, Catalysis, Centrosome, Chromosome Segregation, Controlled Study, Enzyme Binding, Enzyme Localization, Enzyme Phosphorylation, Genetic Stability, Golgi Complex, Human, Human Cell, Interphase, Mouse, Neuroblastoma, Nonhuman, Oncogene, Priority Journal, Protein Expression, Protein Function, Protein Interaction, Protein Variant, Alternative Splicing, Calcium-Binding Proteins, Cell Line, Chromosomal Proteins, Non-Histone, Endopeptidases, Enzyme Activation, Exons, Genomic Instability, Intracellular Membranes, Protein Isoforms, Protein-Serine-Threonine Kinases, Rabbits, Receptor, Recombinant Fusion Proteins, Signal Transduction,
Affiliations:
*** IBB - CNR ***
Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.
Section of Molecular Pathology, Department of Experimental Medicine, University of L'Aquila, Coppito 2, Via Vetoio, L'Aquila 67100, Italy
Department of Biological Science, University of Naples Federico II, Naples, Italy
Neuromed Institute, 86077 Pozzilli, Italy
References:
Not available.
Mol Cell Biol (ISSN: 1098-5549, 0270-7306), 2009 Sep 1; 29(17): 4812-4830.
Export to BibTeX Export to EndNote
Paper type: Journal Article, Research Support, Non-U. S. Gov'T,
Impact factor: 6.057, 5-year impact factor: 6.367
Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-68849121025&partnerID=40&md5=c44b0a54ee181c26e4365897ef9b6d56
Keywords: Cell Cycle Protein 37, Endoplasmic Reticulum Golgi Intermediate Compartment Protein, Gamma Tubulin, Geldanamycin, Heat Shock Protein 90, Lectin, Polo Like Kinase, Protein Tyrosine Kinase A, Protein Tyrosine Phosphatase, Separase, Unclassified Drug, Anaphase, Animal Cell, Article, Catalysis, Centrosome, Chromosome Segregation, Controlled Study, Enzyme Binding, Enzyme Localization, Enzyme Phosphorylation, Genetic Stability, Golgi Complex, Human, Human Cell, Interphase, Mouse, Neuroblastoma, Nonhuman, Oncogene, Priority Journal, Protein Expression, Protein Function, Protein Interaction, Protein Variant, Alternative Splicing, Calcium-Binding Proteins, Cell Line, Chromosomal Proteins, Non-Histone, Endopeptidases, Enzyme Activation, Exons, Genomic Instability, Intracellular Membranes, Protein Isoforms, Protein-Serine-Threonine Kinases, Rabbits, Receptor, Recombinant Fusion Proteins, Signal Transduction,
Affiliations:
*** IBB - CNR ***
Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.
Section of Molecular Pathology, Department of Experimental Medicine, University of L'Aquila, Coppito 2, Via Vetoio, L'Aquila 67100, Italy
Department of Biological Science, University of Naples Federico II, Naples, Italy
Neuromed Institute, 86077 Pozzilli, Italy
References:
Not available.
The alternative TrkAIII splice variant targets the centrosome and promotes genetic instability
The hypoxia-regulated alternative TrkAIII splice variant expressed by human neuroblastomas exhibits oncogenic potential, driven by in-frame exon 6 and 7 alternative splicing, leading to omission of the receptor extracellular immunoglobulin C(1) domain and several N-glycosylation sites. Here, we show that the TrkAIII oncogene promotes genetic instability by interacting with and exhibiting catalytic activity at the centrosome. This function depends upon intracellular TrkAIII accumulation and spontaneous interphase-restricted activation, in cytoplasmic tyrosine kinase (tk) domain orientation, predominantly within structures that closely associate with the fully assembled endoplasmic reticulum intermediate compartment and Golgi network. This facilitates TrkAIII tk-mediated binding of gamma-tubulin, which is regulated by endogenous protein tyrosine phosphatases and geldanamycin-sensitive interaction with Hsp90, paving the way for TrkAIII recruitment to the centrosome. At the centrosome, TrkAIII differentially phosphorylates several centrosome-associated components, increases centrosome interaction with polo kinase 4, and decreases centrosome interaction with separase, the net results of which are centrosome amplification and increased genetic instability. The data characterize TrkAIII as a novel internal membrane-associated centrosome kinase, unveiling an important alternative mechanism to "classical" cell surface oncogenic receptor tk signaling through which stress-regulated alternative TrkAIII splicing influences the oncogenic process.
The hypoxia-regulated alternative TrkAIII splice variant expressed by human neuroblastomas exhibits oncogenic potential, driven by in-frame exon 6 and 7 alternative splicing, leading to omission of the receptor extracellular immunoglobulin C(1) domain and several N-glycosylation sites. Here, we show that the TrkAIII oncogene promotes genetic instability by interacting with and exhibiting catalytic activity at the centrosome. This function depends upon intracellular TrkAIII accumulation and spontaneous interphase-restricted activation, in cytoplasmic tyrosine kinase (tk) domain orientation, predominantly within structures that closely associate with the fully assembled endoplasmic reticulum intermediate compartment and Golgi network. This facilitates TrkAIII tk-mediated binding of gamma-tubulin, which is regulated by endogenous protein tyrosine phosphatases and geldanamycin-sensitive interaction with Hsp90, paving the way for TrkAIII recruitment to the centrosome. At the centrosome, TrkAIII differentially phosphorylates several centrosome-associated components, increases centrosome interaction with polo kinase 4, and decreases centrosome interaction with separase, the net results of which are centrosome amplification and increased genetic instability. The data characterize TrkAIII as a novel internal membrane-associated centrosome kinase, unveiling an important alternative mechanism to "classical" cell surface oncogenic receptor tk signaling through which stress-regulated alternative TrkAIII splicing influences the oncogenic process.
The alternative TrkAIII splice variant targets the centrosome and promotes genetic instability
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The alternative TrkAIII splice variant targets the centrosome and promotes genetic instability
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Farina AR, Tacconelli A, Cappabianca L, Cea G, Chioda A, Romanelli A, Pensato S, Pedone C, Gulino A, Mackay AR
* The neuroblastoma tumour-suppressor TrkAI and its oncogenic alternative TrkAIII splice variant exhibit geldanamycin-sensitive interactions with Hsp90 in human neuroblastoma cells (494 views)
Oncogene (ISSN: 1476-5594, 0950-9232), 2009 Nov 19; 28(46): 4075-4094.
Impact Factor: 7.135
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* The neuroblastoma tumour-suppressor TrkAI and its oncogenic alternative TrkAIII splice variant exhibit geldanamycin-sensitive interactions with Hsp90 in human neuroblastoma cells (494 views)
Oncogene (ISSN: 1476-5594, 0950-9232), 2009 Nov 19; 28(46): 4075-4094.
Impact Factor: 7.135
View Export to BibTeX Export to EndNote
1 Records (1 excluding Abstracts).
Total impact factor: 7.135 (7.135 excluding Abstracts).
Total 5 year impact factor: 6.73 (6.73 excluding Abstracts).
Total impact factor: 7.135 (7.135 excluding Abstracts).
Total 5 year impact factor: 6.73 (6.73 excluding Abstracts).
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