TrkA alternative splicing: a regulated tumor-promoting switch in human neuroblastoma.
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-kappaB 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-kappaB tumor-promoting signals during tumor progression.
Department of Experimental Medicine, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy.
Antonella
A
Tacconelli
Antonietta R
AR
Farina
Lucia
L
Cappabianca
Giuseppina
G
Desantis
Alessandra
A
Tessitore
Antonella
A
Vetuschi
Roberta
R
Sferra
Nadia
N
Rucci
Beatrice
B
Argenti
Isabella
I
Screpanti
Alberto
A
Gulino
Andrew R
AR
Mackay
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D004317:Doxorubicin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology; D009447:Neuroblastoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma; D011485:Protein Binding; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D010738:Type C Phospholipases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D016328:NF-kappa B; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D004317:Doxorubicin; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D020917:Receptor, trkA; D010738:Type C Phospholipases; D051966:Phospholipase C gamma