The alternative TrkAIII splice variant targets the centrosome and promotes genetic instability(358 views) Farina AR, Tacconelli A, Cappabianca L, Cea G, Panella S, Chioda A, Romanelli A, Pedone C, Gulino A, Mackay AR
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
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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 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