TrkA alternative splicing: A regulated tumor-promoting switch in human neuroblastoma

Antonella Tacconelli, Antonietta R. Farina, Lucia Cappabianca, Giuseppina DeSantis, Alessandra Tessitore, Antonella Vetuschi, Roberta Sferra, Nadia Rucci, Beatrice Argenti, Isabella Screpanti, Alberto Gulino, Andrew R. Mackay

Research output: Contribution to journalArticlepeer-review


We identify a novel alternative TrkA splice variant, TrkAIII, with deletion of exons 6, 7, and 9 and functional extracellular IG-C1 and N-glycosylation domains, that exhibits expression restricted to undifferentiated early neural progenitors, human neuroblastomas (NBs), and a subset of other neural crest-derived tumors. This NGF-unresponsive isoform is oncogenic in NIH3T3 cells and promotes tumorigenic NB cell behavior in vitro and in vivo (cell survival, xenograft growth, angiogenesis) resulting from spontaneous tyrosine kinase activity and IP3K/Akt/NF-κB but not Ras/MAPK signaling. TrkAIII antagonizes NGF/TrkAI signaling, which is responsible for NB growth arrest and differentiation through Ras/MAPK, and its expression is promoted by hypoxia at the expense of NGF-responsive receptors, providing a mechanism for converting NGF/TrkA/Ras/MAPK antioncogenic signals to TrkAIII/IP3K/Akt/NF-κB tumor-promoting signals during tumor progression.

Original languageEnglish
Pages (from-to)347-360
Number of pages14
JournalCancer Cell
Issue number4
Publication statusPublished - Oct 2004

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology


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