NTRK3 (neurotrophic tyrosine kinase, receptor, type 3)

2004-04-01   Stevan Knezevich  

BC Cancer Research Centre (BCCRC), Vancouver, British Columbia, Canada

Identity

HGNC
NTRK3
LOCATION
15q25.3
LOCUSID
4916
ALIAS
GP145-TrkC,TRKC,gp145(trkC)
FUSION GENES
Show Gene Fusions

DNA/RNA

Description

The gene for NTRK3 is located on chromosome 15 q25 and is encoded by 20 exons. Exon 1 codes for the translation initiation codon (ATG) and the signal sequence (SS), while the stop codon is located in exon 18. Exons 1 to 4 encode the Neurotrophin ligand binding domain (also known a the Immunoglobulin - like domain 2). Exons 10 and 11 encode the transmembrane domain while the tyrosine kinase domain is encoded by exons 13-18.

Pseudogene

Variant transcripts exist for NTRK3, which have been termed non-catalytic (NC) as they do not contain enough sequence to mount an appropriate autophosphorylation event. These have been named NTRK3-NC1 and NTRK3 NC2.

Proteins

Atlas Image
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.

    • 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.

    Implicated in

    Entity name
    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.
    Entity name
    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).
    Hybrid gene
    ETV6-NTRK3
    Atlas Image
    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.
    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.
    Entity name
    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 gene
    ETV6-NTRK3
    Please see above diagrams and explanations for the protein and proposed oncogenic mechanism.

    Breakpoints

    Atlas Image

    Article Bibliography

    Pubmed IDLast YearTitleAuthors
    78529931994The Trk family of neurotrophin receptors.Barbacid M et al
    97780531998Genomic characterization of the human trkC gene.Ichaso N et al
    94627531998A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma.Knezevich SR et al
    78062111994Molecular cloning of the cDNA for human TrkC (NTRK3), chromosomal assignment, and evidence for a splice variant.McGregor LM et al
    98027001998Differential expression of TrkC catalytic and noncatalytic isoforms suggests that they act independently or in association.Menn B et al
    78091371994Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma.Segal RA et al
    124507922002Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma.Tognon C et al

    Other Information

    Locus ID:

    NCBI: 4916
    MIM: 191316
    HGNC: 8033
    Ensembl: ENSG00000140538

    Variants:

    dbSNP: 4916
    ClinVar: 4916
    TCGA: ENSG00000140538
    COSMIC: NTRK3

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000140538ENST00000317501Q16288
    ENSG00000140538ENST00000317501Q96CY4
    ENSG00000140538ENST00000355254Q16288
    ENSG00000140538ENST00000355254X5DNW6
    ENSG00000140538ENST00000357724Q16288
    ENSG00000140538ENST00000360948Q16288
    ENSG00000140538ENST00000360948X5D2R1
    ENSG00000140538ENST00000394480Q16288
    ENSG00000140538ENST00000394480X5D7M5
    ENSG00000140538ENST00000540489Q16288
    ENSG00000140538ENST00000540489Q96CY4
    ENSG00000140538ENST00000542733B7Z7U4
    ENSG00000140538ENST00000557856Q16288
    ENSG00000140538ENST00000557856X5DNW6
    ENSG00000140538ENST00000558306A0A087WX31
    ENSG00000140538ENST00000558576R4GMR8
    ENSG00000140538ENST00000558676H0YM90
    ENSG00000140538ENST00000559188R4GNH5
    ENSG00000140538ENST00000560017R4GN40
    ENSG00000140538ENST00000626019A0A0D9SFP6
    ENSG00000140538ENST00000629765Q16288
    ENSG00000140538ENST00000629765X5D2R1

    Expression (GTEx)

    0
    5
    10
    15
    20
    25
    30
    35
    Adipose - Subcutaneous
    Adipose - Visceral
    Adrenal Gland
    Artery - Aorta
    Artery - Tibial
    Bladder
    Brain - Amygdala
    Brain - Anterior cingulate cortex
    Brain - Caudate
    Brain - Cerebellar Hemisphere
    Brain - Cerebellum
    Brain - Cortex
    Brain - Frontal Cortex
    Brain - Hippocampus
    Brain - Hypothalamus
    Brain - Nucleus accumbens
    Brain - Putamen
    Brain - Spinal cord
    Brain - Substantia nigra
    Breast - Mammary Tissue
    Cells - Cultured fibroblasts
    Cells - EBV - transformed lymphocytes
    Cervix - Ectocervix
    Cervix - Endocervix
    Colon - Sigmoid
    Colon - Transverse
    Esophagus - Gastroesophageal Junction
    Esophagus - Mucosa
    Esophagus - Muscularis
    Fallopian Tube
    Heart - Atrial Appendage
    Heart - Left Ventricle
    Kidney - Cortex
    Kidney - Medulla
    Liver
    Lung
    Minor Salivary Gland
    Muscle - Skeletal
    Nerve - Tibial
    Ovary
    Pancreas
    Pituitary
    Prostate
    Skin - Not Sun Exposed
    Skin - Sun Exposed
    Small Intestine - Terminal Ileum
    Spleen
    Stomach
    Testis
    Thyroid
    Uterus
    Vagina
    Whole Blood

    Pathways

    PathwaySourceExternal ID
    Neurotrophin signaling pathwayKEGGko04722
    Neurotrophin signaling pathwayKEGGhsa04722
    Central carbon metabolism in cancerKEGGhsa05230
    Central carbon metabolism in cancerKEGGko05230

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High
    cerebral cortex
    cerebellum
    hippocampus
    caudate
    thyroid gland
    parathyroid gland
    adrenal gland
    nasopharynx
    bronchus
    lung
    oral mucosa
    salivary gland
    esophagus
    stomach 1
    stomach 2
    duodenum
    small intestine
    colon
    rectum
    liver
    gallbladder
    pancreas
    kidney
    urinary bladder
    testis
    epididymis
    seminal vesicle
    prostate
    vagina
    ovary
    fallopian tube
    endometrium 1
    endometrium 2
    cervix, uterine
    placenta
    breast
    heart muscle
    smooth muscle
    skeletal muscle
    soft tissue 2
    adipose tissue
    skin 1
    appendix
    spleen
    lymph node
    tonsil
    bone marrow

    PharmGKB

    Entity IDNameTypeEvidenceAssociationPKPDPMIDs
    PA166182733larotrectinib sulfateChemicalLabelAnnotationassociated
    PA166190161entrectinibChemicalLabelAnnotationassociated
    PA447199Bipolar DisorderDiseaseLiterature, MultilinkAnnotationassociated24718920

    References

    Pubmed IDYearTitleCitations
    385932762024NTRK3 exhibits a pro-oncogenic function in upper tract urothelial carcinomas.0
    385932762024NTRK3 exhibits a pro-oncogenic function in upper tract urothelial carcinomas.0
    372720572023Expression and prognostic impact of NTF3 and TrkC in hepatocellular carcinoma.0
    374150522023High-grade non-intestinal type sinonasal adenocarcinoma with ETV6::NTRK3 fusion, distinct from secretory carcinoma by immunoprofile and morphology.1
    376974382023Srsf1 and Elavl1 act antagonistically on neuronal fate choice in the developing neocortex by controlling TrkC receptor isoform expression.0
    372720572023Expression and prognostic impact of NTF3 and TrkC in hepatocellular carcinoma.0
    374150522023High-grade non-intestinal type sinonasal adenocarcinoma with ETV6::NTRK3 fusion, distinct from secretory carcinoma by immunoprofile and morphology.1
    376974382023Srsf1 and Elavl1 act antagonistically on neuronal fate choice in the developing neocortex by controlling TrkC receptor isoform expression.0
    351526312022[Clinicopathological features of NTRK3 gene rearrangement papillary thyroid carcinoma].0
    355367422022Selective activation and down-regulation of Trk receptors by neurotrophins in human neurons co-expressing TrkB and TrkC.9
    357371552022Prediction of EVT6-NTRK3-Dependent Papillary Thyroid Cancer Using Minor Expression Profile.1
    361712072022TrkC, a novel prognostic marker, induces and maintains cell survival and metastatic dissemination of Ewing sarcoma by inhibiting EWSR1-FLI1 degradation.3
    351526312022[Clinicopathological features of NTRK3 gene rearrangement papillary thyroid carcinoma].0
    355367422022Selective activation and down-regulation of Trk receptors by neurotrophins in human neurons co-expressing TrkB and TrkC.9
    357371552022Prediction of EVT6-NTRK3-Dependent Papillary Thyroid Cancer Using Minor Expression Profile.1

    Citation

    Stevan Knezevich

    NTRK3 (neurotrophic tyrosine kinase, receptor, type 3)

    Atlas Genet Cytogenet Oncol Haematol. 2004-04-01

    Online version: http://atlasgeneticsoncology.org/gene/433/teaching-explorer/case-report-explorer/gene-explorer/