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NTRK3 (neurotrophic tyrosine kinase, receptor, type 3)

Identity

Other namesTrkC
Neurotrophin 3 Receptor
HGNC (Hugo) NTRK3
LocusID (NCBI) 4916
Location 15q25.3
Location_base_pair Starts at 88520596 and ends at 88799962 bp from pter ( according to hg19-Feb_2009)  [Mapping]

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.

Protein

 
  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 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 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).
     
    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.
    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.
      
    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.
      

    Other Leukemias implicated (Data extracted from papers in the Atlas)

    Leukemias 11q23ChildAMLID1615

    Other Solid tumors implicated (Data extracted from papers in the Atlas)

    Solid Tumors AmeloblastomID5945 MedulloblastomaID5065 rhab5004

    External links

    Nomenclature
    HGNC (Hugo)NTRK3   8033
    Cards
    AtlasNTRK3ID433
    Entrez_Gene (NCBI)NTRK3  4916  neurotrophic tyrosine kinase, receptor, type 3
    GeneCards (Weizmann)NTRK3
    Ensembl (Hinxton)ENSG00000140538 [Gene_View]  chr15:88520596-88799962 [Contig_View]  NTRK3 [Vega]
    ICGC DataPortalENSG00000140538
    AceView (NCBI)NTRK3
    Genatlas (Paris)NTRK3
    WikiGenes4916
    SOURCE (Princeton)NM_001007156 NM_001012338 NM_001243101 NM_002530
    Genomic and cartography
    GoldenPath (UCSC)NTRK3  -  15q25.3   chr15:88520596-88799962 -  15q24-q25   [Description]    (hg19-Feb_2009)
    EnsemblNTRK3 - 15q24-q25 [CytoView]
    Mapping of homologs : NCBINTRK3 [Mapview]
    OMIM191316   
    Gene and transcription
    Genbank (Entrez)AF052184 AF058389 AF058390 AF125808 AI613045
    RefSeq transcript (Entrez)NM_001007156 NM_001012338 NM_001243101 NM_002530
    RefSeq genomic (Entrez)AC_000147 NC_000015 NC_018926 NG_029619 NT_010194 NW_001838222 NW_004929399
    Consensus coding sequences : CCDS (NCBI)NTRK3
    Cluster EST : UnigeneHs.706364 [ NCBI ]
    CGAP (NCI)Hs.706364
    Alternative Splicing : Fast-db (Paris)GSHG0010697
    Alternative Splicing GalleryENSG00000140538
    Gene ExpressionNTRK3 [ NCBI-GEO ]     NTRK3 [ SEEK ]   NTRK3 [ MEM ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ16288 (Uniprot)
    NextProtQ16288  [Medical]
    With graphics : InterProQ16288
    Splice isoforms : SwissVarQ16288 (Swissvar)
    Catalytic activity : Enzyme2.7.10.1 [ Enzyme-Expasy ]   2.7.10.12.7.10.1 [ IntEnz-EBI ]   2.7.10.1 [ BRENDA ]   2.7.10.1 [ KEGG ]   
    Domaine pattern : Prosite (Expaxy)IG_LIKE (PS50835)    LRR (PS51450)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_TYR (PS00109)    RECEPTOR_TYR_KIN_II (PS00239)   
    Domains : Interpro (EBI)Cys-rich_flank_reg_C    Ig-like_dom    Ig-like_fold    Ig_I-set    Ig_sub    Immunoglobulin    Kinase-like_dom    Leu-rich_rpt    LRR-contain_N    Prot_kinase_dom    Protein_kinase_ATP_BS    Ser-Thr/Tyr_kinase_cat_dom    Tyr_kin_neurotrophic_rcpt_3    Tyr_kinase_AS    Tyr_kinase_cat_dom    Tyr_kinase_NGF_rcpt    Tyr_kinase_rcpt_2_CS   
    Related proteins : CluSTrQ16288
    Domain families : Pfam (Sanger)I-set (PF07679)    ig (PF00047)    LRR_8 (PF13855)    LRRNT (PF01462)    Pkinase_Tyr (PF07714)   
    Domain families : Pfam (NCBI)pfam07679    pfam00047    pfam13855    pfam01462    pfam07714   
    Domain families : Smart (EMBL)IG (SM00409)  LRRCT (SM00082)  LRRNT (SM00013)  TyrKc (SM00219)  
    DMDM Disease mutations4916
    Blocks (Seattle)Q16288
    PDB (SRS)1WWC    3V5Q   
    PDB (PDBSum)1WWC    3V5Q   
    PDB (IMB)1WWC    3V5Q   
    PDB (RSDB)1WWC    3V5Q   
    Human Protein AtlasENSG00000140538
    Peptide AtlasQ16288
    HPRD01870
    IPIIPI00000824   IPI00185466   IPI00289961   IPI01012361   IPI00103437   IPI00376986   IPI01011028   IPI01011984   
    Protein Interaction databases
    DIP (DOE-UCLA)Q16288
    IntAct (EBI)Q16288
    FunCoupENSG00000140538
    BioGRIDNTRK3
    IntegromeDBNTRK3
    STRING (EMBL)NTRK3
    Ontologies - Pathways
    QuickGOQ16288
    Ontology : AmiGOactivation of MAPK activity  neuron migration  negative regulation of protein phosphorylation  p53 binding  transmembrane receptor protein tyrosine kinase activity  neurotrophin receptor activity  ATP binding  cytoplasm  integral component of plasma membrane  transmembrane receptor protein tyrosine kinase signaling pathway  positive regulation of cell proliferation  positive regulation of gene expression  peptidyl-tyrosine phosphorylation  modulation by virus of host transcription  positive regulation of cell migration  activation of protein kinase B activity  activation of Ras GTPase activity  positive regulation of peptidyl-serine phosphorylation  neurotrophin signaling pathway  neurotrophin signaling pathway  mechanoreceptor differentiation  neurotrophin binding  receptor complex  response to ethanol  protein autophosphorylation  ephrin receptor binding  neuron fate specification  response to axon injury  positive regulation of axon extension involved in regeneration  negative regulation of astrocyte differentiation  positive regulation of positive chemotaxis  response to corticosterone  negative regulation of cell death  cellular response to retinoic acid  cochlea development  positive regulation of actin cytoskeleton reorganization  
    Ontology : EGO-EBIactivation of MAPK activity  neuron migration  negative regulation of protein phosphorylation  p53 binding  transmembrane receptor protein tyrosine kinase activity  neurotrophin receptor activity  ATP binding  cytoplasm  integral component of plasma membrane  transmembrane receptor protein tyrosine kinase signaling pathway  positive regulation of cell proliferation  positive regulation of gene expression  peptidyl-tyrosine phosphorylation  modulation by virus of host transcription  positive regulation of cell migration  activation of protein kinase B activity  activation of Ras GTPase activity  positive regulation of peptidyl-serine phosphorylation  neurotrophin signaling pathway  neurotrophin signaling pathway  mechanoreceptor differentiation  neurotrophin binding  receptor complex  response to ethanol  protein autophosphorylation  ephrin receptor binding  neuron fate specification  response to axon injury  positive regulation of axon extension involved in regeneration  negative regulation of astrocyte differentiation  positive regulation of positive chemotaxis  response to corticosterone  negative regulation of cell death  cellular response to retinoic acid  cochlea development  positive regulation of actin cytoskeleton reorganization  
    Pathways : KEGGNeurotrophin signaling pathway   
    Protein Interaction DatabaseNTRK3
    Wikipedia pathwaysNTRK3
    Gene fusion - rearrangments
    Rearrangement : COSMICNTRK3 [15q25.3]  -  ETV6 [12p13.2]
    Rearrangement : TICdbETV6 [12p13.2]  -  NTRK3 [4q31.21]
    Polymorphisms : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)NTRK3
    SNP (GeneSNP Utah)NTRK3
    SNP : HGBaseNTRK3
    Genetic variants : HAPMAPNTRK3
    1000_GenomesNTRK3 
    ICGC programENSG00000140538 
    Cancer Gene: CensusNTRK3 
    CONAN: Copy Number AnalysisNTRK3 
    Somatic Mutations in Cancer : COSMICNTRK3 
    LOVD (Leiden Open Variation Database)Whole genome datasets
    LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
    LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
    DECIPHER (Syndromes)15:88520596-88799962
    Mutations and Diseases : HGMDNTRK3
    OMIM191316   
    MedgenNTRK3
    GENETestsNTRK3
    Disease Genetic AssociationNTRK3
    Huge Navigator NTRK3 [HugePedia]  NTRK3 [HugeCancerGEM]
    Genomic VariantsNTRK3  NTRK3 [DGVbeta]
    Exome VariantNTRK3
    dbVarNTRK3
    ClinVarNTRK3
    snp3D : Map Gene to Disease4916
    General knowledge
    Homologs : HomoloGeneNTRK3
    Homology/Alignments : Family Browser (UCSC)NTRK3
    Phylogenetic Trees/Animal Genes : TreeFamNTRK3
    Chemical/Protein Interactions : CTD4916
    Chemical/Pharm GKB GenePA31819
    Clinical trialNTRK3
    Cancer Resource (Charite)ENSG00000140538
    Other databases
    Probes
    Litterature
    PubMed114 Pubmed reference(s) in Entrez
    CoreMineNTRK3
    GoPubMedNTRK3
    iHOPNTRK3

    Bibliography

    The Trk family of neurotrophin receptors.
    Barbacid M
    Journal of neurobiology. 1994 ; 25 (11) : 1386-1403.
    PMID 7852993
     
    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
     
    Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma.
    Segal RA, Goumnerova LC, Kwon YK, Stiles CD, Pomeroy SL
    Proceedings of the National Academy of Sciences of the United States of America. 1994 ; 91 (26) : 12867-12871.
    PMID 7809137
     
    Genomic characterization of the human trkC gene.
    Ichaso N, Rodriguez RE, Martin-Zanca D, Gonzalez-Sarmiento R
    Oncogene. 1998 ; 17 (14) : 1871-1875.
    PMID 9778053
     
    ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma.
    Knezevich SR, Garnett MJ, Pysher TJ, Beckwith JB, Grundy PE, Sorensen PH
    Cancer research. 1998 ; 58 (22) : 5046-5048.
    PMID 9823307
     
    A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma.
    Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PH
    Nature genetics. 1998 ; 18 (2) : 184-187.
    PMID 9462753
     
    Differential expression of TrkC catalytic and noncatalytic isoforms suggests that they act independently or in association.
    Menn B, Timsit S, Calothy G, Lamballe F
    The Journal of comparative neurology. 1998 ; 401 (1) : 47-64.
    PMID 9802700
     
    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
    Cancer cell. 2002 ; 2 (5) : 367-376.
    PMID 12450792
     
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    Contributor(s)

    Written04-2004Stevan Knezevich

    Citation

    This paper should be referenced as such :
    Knezevich, S
    NTRK3 (neurotrophic tyrosine kinase, receptor, type 3)
    Atlas Genet Cytogenet Oncol Haematol. 2004;8(2):73-75.
    Free online version   Free pdf version   [Bibliographic record ]
    URL : http://AtlasGeneticsOncology.org/Genes/NTRK3ID433.html

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    indexed on : Sat Nov 8 16:56:53 CET 2014

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