The alternative TrkAIII splice variant targets the centrosome and promotes genetic instability

Antonietta Rosella Farina, Antonella Tacconelli, Lucia Cappabianca, Gesilia Cea, Sonia Panella, Antonella Chioda, Alessandra Romanelli, Carlo Pedone, Alberto Gulino, Andrew Reay Mackay

Research output: Contribution to journalArticlepeer-review

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 γ-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 stressregulated alternative TrkAIII splicing influences the oncogenic process.

Original languageEnglish
Pages (from-to)4812-4830
Number of pages19
JournalMolecular and Cellular Biology
Volume29
Issue number17
DOIs
Publication statusPublished - Sep 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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