Author/Authors :
Tacconelli، نويسنده , , Antonella and Farina، نويسنده , , Antonietta R. and Cappabianca، نويسنده , , Lucia and DeSantis، نويسنده , , Giuseppina and Tessitore، نويسنده , , Alessandra and Vetuschi، نويسنده , , Antonella and Sferra، نويسنده , , Roberta and Rucci، نويسنده , , Nadia and Argenti، نويسنده , , Beatrice and Screpanti، نويسنده , , Isabella and Gulino، نويسنده , , Alberto and Mackay، نويسنده , , Andrew R.، نويسنده ,
Abstract :
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.
