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The alternative TrkAIII splice variant targets the centrosome and promotes genetic instability.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2009 Sep; Vol. 29 (17), pp. 4812-30. Date of Electronic Publication: 2009 Jun 29. - Publication Year :
- 2009
-
Abstract
- 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.
- Subjects :
- Animals
Calcium-Binding Proteins genetics
Calcium-Binding Proteins metabolism
Cell Cycle physiology
Cell Cycle Proteins genetics
Cell Cycle Proteins metabolism
Cell Line
Chromosomal Proteins, Non-Histone genetics
Chromosomal Proteins, Non-Histone metabolism
Endopeptidases genetics
Endopeptidases metabolism
Enzyme Activation
Exons
Humans
Intracellular Membranes metabolism
Mice
Neuroblastoma genetics
Neuroblastoma metabolism
Protein Serine-Threonine Kinases genetics
Protein Serine-Threonine Kinases metabolism
Rabbits
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins metabolism
Separase
Signal Transduction physiology
Tubulin metabolism
Alternative Splicing
Centrosome metabolism
Genomic Instability
Protein Isoforms genetics
Protein Isoforms metabolism
Receptor, trkA genetics
Receptor, trkA metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5549
- Volume :
- 29
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 19564412
- Full Text :
- https://doi.org/10.1128/MCB.00352-09