The chimeric protein tyrosine kinase ETV6-NTRK3 requires both Ras-Erk1/2 and PI3-kinase-Akt signaling for fibroblast transformation.
There is increasing interest in the potential role of the NTRK family of neurotrophin receptors in human neoplasia. These receptor protein tyrosine kinases (PTKs) are well-known mediators of neuronal cell survival and differentiation, but altered NTRK signaling has also been implicated in mesenchymal, hematopoietic, and epithelial malignancies. We recently identified a novel gene fusion involving one of the neurotrophin receptor genes, NTRK3, in the pediatric solid tumor, congenital fibrosarcoma. In these tumors (and subsequently demonstrated in several other human malignancies), a t(12;15)(p13;q25) rearrangement fuses the 3' portion of the ETV6 gene with exons encoding the PTK domain of NTRK3. The resulting ETV6-NTRK3 fusion protein functions as a chimeric PTK with potent transforming activity. However, previous studies failed to detect interactions between ETV6-NTRK3 and molecules known to link wild-type NTRK3 to its two major effector pathways, namely the Ras-Raf1-Mek1-Erk1/2 mitogenic pathway or the phosphatidylinositol 3'-kinase pathway leading to activation of the AKT survival factor. Therefore, it remains unknown whether ETV6-NTRK3 transformation involves altered NTRK3 signaling. We now report that ETV6-NTRK3 expression in NIH3T3 cells leads to constitutive activation of Mek1 and Akt, as well as to constitutively high expression of cyclin D1. ETV6-NTRK3-induced soft agar colony formation was almost completely abolished by inhibition of either the Ras-Raf1-Mek1-Erk1/2 or the phosphatidylinositol 3'-kinase-Akt pathway. Moreover, this inhibition dramatically reduced expression of cyclin D1. Our results indicate that ETV6-NTRK3 transformation involves a link between known NTRK3 signaling pathways and aberrant cell cycle progression and that Mek1 and Akt activation act synergistically to mediate these effects.
Tognon
C
C
Department of Pathology, BC Research Institute for Children's and Women's Health, Vancouver, British Columbia, V6H 3V4.
Garnett
M
M
Kenward
E
E
Kay
R
R
Morrison
K
K
Sorensen
P H
PH
D016475:3T3 Cells / Q000201:enzymology / Q000502:physiology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism*; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D050783:Proto-Oncogene Proteins c-ets; D020812:Receptor, trkC / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000097764:ETS Translocation Variant 6 Protein
D019938:Cyclin D1; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D050783:Proto-Oncogene Proteins c-ets; D020812:Receptor, trkC; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D018631:ras Proteins; D000097764:ETS Translocation Variant 6 Protein; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse