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| | The NTRK3 protein is composed of several regions. Starting at the amino terminus is the signal sequence (SS) responsible for directing the newly translated protein to the cell surface. Next is the Extracellular Ligand Binding Domain (ECD-LB), which binds Neurotrophin 3 and subsequent homo-dimerization with autophosphorylation of key tyrosine residues. The transmembrane domain (TM) spans the plasma membrane. The intracellular portion is composed of the protein tyrosine kinase domain (PTK) which has both the key tyrosines for autophosphorylation as well as tyrosines that are phosphorylated and act as activators of downstream molecules including Shc, PI3-Kinase and PLC-g. |
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| Description | 145 kDa protein, located on plasma membrane with an extra-cellular ligand binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. Ligand for NTRK3 is Neurotrophin 3; after binding to NTRK3, it causes dimerization and autophosphorylation of specific tyrosine phosphates, which in turn act as anchors and activators of downstream molecules such as Shc, PI3-K and PLC-g. |
| Expression | Primarily in central nervous system tissue with specific emphasis in hippocampus, cerebral cortex, and the granular cell layer of the cerebellum. In addition, there is a minor amount expressed in a variety of other tissues. |
| Localisation | Plasma membrane; transmembrane receptor tyrosine kinase. |
| Function | Tyrosine kinase cell surface receptor responsible for the proliferation and differentiation of neuraly derived cells; |
| Homology | Acid sequence is 97% and 98% homologous to the rat and porcine TRKC sequences, respectively. |
| Entity | Medulloblastoma |
| Note | Over-expression of NTRK3 mRNA was found to be associated with a much favorable prognosis over medulloblastomas with a comparatively low expression of NTRK3. |
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| Entity | Congenital Fibrosarcoma (CFS) and Congenital Mesoblastic Nephroma-cellular variant (cellular CMN). |
| Disease | CFS and cellular CMN are pediatric tumors of spindle cell origin (mesoblastic origin). CFS primarily presents at birth up to 2 years of age, usually affecting the extremities. Cellular CMN, on the other hand is a pediatric spindle cell tumor of the kidney. |
| Prognosis | The presence of the ETV6-NTRK3 gene fusion in both CFS and cellular CMN indicate an excellent prognosis when compared to their histologically similar and more aggressive counterparts. |
| Cytogenetics | The ETV6-NTRK3 gene fusion is the result of a t(12;15)(p13;q25). |
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| The amino terminus is composed of the first 5 exons from ETV6, which carries the Helix-Loop-Helix Domain (HLH) responsible for dimerization. The remainder of the protein is composed of the Protein Tyrosine Kinase domain from NTRK3. The arrow represents the point at which the ETV6 contribution ends and the NTRK3 contribution begins. |
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| Hybrid/Mutated Gene | ETV6-NTRK3 |
| Oncogenesis | Current speculation regarding the oncogenic mechanism of the fusion protein is related to its putative activation of the MAP Kinase pathway with resultant activation of various downstream proteins such as transcription factors. Native NTRK3 requires extracellular ligand binding of Neurotrophin 3 prior to its dimerization and autophosphorylation. ETV-6-NTRK3, however, bypasses this requirement as it contains the HLH domain from ETV6 which allows the molecule to dimerize in the absence of Neurotrophin 3 and thus remain in a constitutively activated (phosphorylated) state. Once again, the presence of ETV6-NTRK3 seems to make these particular neoplasms behave more indolent than their aggressive Ductal Carinoma counterparts, which do not harbor the ETV6-NTRK3 gene fusion. |
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| Entity | Secretory Breast Carcinoma (a variant of ductal carcinoma of the breast) |
| Note | Virtually all cases of CFS and cellular CMN to date have been associated with the ETV6-NTRK3 gene fusion. In addition these malignancies almost always have an additional copy of chromosome 11. This additional copy of chromosome 11 is not found in secretory breast carcinoma. Finally, the ETV6-NTRK3 gene fusion was found in secretory breast carcinomas of all ages (the youngest case being a 6 year old female). |
| Disease | Secretory Breast Carcinoma is an epithelially derived breast cancer, as opposed to the mesoblastic CFS and cellular CMN above. It can occur in the pediatric population and much more commonly in adults. |
| Cytogenetics | The ETV6-NTRK3 gene fusion is the result of a t(12;15)(p13;q25). |
| Hybrid/Mutated Gene | ETV6-NTRK3
Please see above diagrams and explanations for the protein and proposed oncogenic mechanism. |
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| The Trk family of neurotrophin receptors. |
| Barbacid M |
| Journal of neurobiology. 1994 ; 25 (11) : 1386-1403. |
| PMID 7852993 |
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| Molecular cloning of the cDNA for human TrkC (NTRK3), chromosomal assignment, and evidence for a splice variant. |
| McGregor LM, Baylin SB, Griffin CA, Hawkins AL, Nelkin BD |
| Genomics. 1994 ; 22 (2) : 267-272. |
| PMID 7806211 |
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| Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma. |
| Segal RA, Goumnerova LC, Kwon YK, Stiles CD, Pomeroy SL |
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| PMID 7809137 |
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| PMID 9778053 |
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| ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. |
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| PMID 9823307 |
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| A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. |
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| Nature genetics. 1998 ; 18 (2) : 184-187. |
| PMID 9462753 |
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| Differential expression of TrkC catalytic and noncatalytic isoforms suggests that they act independently or in association. |
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| PMID 9802700 |
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| Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. |
| Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, Becker L, Carneiro F, MacPherson N, Horsman D, Poremba C, Sorensen PH |
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| PMID 12450792 |
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