TY - JOUR
T1 - TrkA alternative splicing
T2 - A regulated tumor-promoting switch in human neuroblastoma
AU - Tacconelli, Antonella
AU - Farina, Antonietta R.
AU - Cappabianca, Lucia
AU - DeSantis, Giuseppina
AU - Tessitore, Alessandra
AU - Vetuschi, Antonella
AU - Sferra, Roberta
AU - Rucci, Nadia
AU - Argenti, Beatrice
AU - Screpanti, Isabella
AU - Gulino, Alberto
AU - Mackay, Andrew R.
PY - 2004/10
Y1 - 2004/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ccr.2004.09.011
DO - 10.1016/j.ccr.2004.09.011
M3 - Article
C2 - 15488758
AN - SCOPUS:5444258188
SN - 1535-6108
VL - 6
SP - 347
EP - 360
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -