NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2)

2007-12-01   Nadia Gabellini 

University of Padua, Department of Biological Chemistry, Viale G. Colombo, 3; 35131, Padua, Italy




Atlas Image
Figure 1: The horizontal bar represents NTRK2 gene (355,039 bp). Vertical bars depict the exons 1-24 (red: translated regions, blue: 5 and 3 UTR regions).
Table 1: NTRK2 exons and size (bp).


NTRK2 gene is comprised between 86,473,286-86,828,325 bp of chromosome 9, with plus strand orientation. The start codon is located on exon 5. Alternative stop codons are placed on terminal exons 16, 19 and 24.


According to AceView (NCBI), six alternative promoters may control transcription of the complex NTRK2 locus. There are at least 18 mRNA variants supported by cDNA clones, potentially encoding 12 complete proteins. Variants may include 8 different terminal exons with alternative polyadenylation sites. Truncation at the 5 end or 3 end, alternative splicing, intron retention, occurrence of 5 cassette exons, and different exon boundaries introduce additional differences.
Five confirmed mRNA variants (a, b, c, d, e) are reported (NCBI accessions: NM_006180.3; NM_001007097.1; NM_001018064.1; NM_001018065.1; NM_001018066.1). The mRNA variant (a) encodes the full-length protein; variant (c) is slightly shorter excluding the small internal exon 17. Of particular importance are the truncated isoforms lacking the catalytic tyrosine kinase domain generated by the inclusion of alternate terminal exon 16 (b) or exon 19 (d) and (e).





Three TrkB isoforms are reported by UniProt/Swiss-Prot:
1. The long isoform TrkB, including the tyrosine kinase domain (ID Q16620-1; variant c).
2. The truncated isoform TrkB-T1 lacking the tyrosine kinase domain (ID Q16620-2; variant b).
3. The truncated isoform TrkB-T-Shc lacking the tyrosine kinase domain but retaining the Shc site (ID Q16620-3; variant e).
Atlas Image
The predicted domains of TrkB (variant c): Signal Peptide (SP, AA 1-31); Leucine Rich Repeat N-Terminal domain (LRRNT, AA 31-65); Leucine-rich Repeats (LRR, AA 72-93, 96-117, 116-138); Leucine Rich Repeat C-Terminal domain (LRRCT, AA 148-195); Immunoglobulin C-2 Type 1 domain (IGC2-1, AA 197-282); Immunoglobulin C-2-type 2 domain (IGC2-2, AA 295-365); Transmembrane (TM, AA 431-454); the Protein Kinase domain (TyrKc, AA 538-807). In addition the site of interaction with SHC1 (Shc, AA 516) and with Phospho-Lipase C-gamma-1 (AA PLC-gamma, 817) are indicated.


The unprocessed precursor of the full-length TrkB (a) consists of 838 AA. Variant (c) excludes 16 AA of unknown function, located downstream of the transmembrane segment.
The N-terminal portion (AA 32-430) is potentially extracellular and includes several N-glycosylation sites (AA 67, 121, 254). It follows a single transmembrane segment (AA 432-454). The C-terminal portion is cytosolic (AA 455-822) and comprises the Protein Kinase domain. This region includes the ATP binding site (AA 544-552) and several sites of autophosphorylation such as Tyr-516/702/706/707/817 (AA position refers to variant c).
The truncated Trkb-T1 (b) is composed of 477 AA. TrkB-T-Shc variants d and e consist of 553 AA and 537 AA, respectively. Truncated isoforms TrkB-T1 and TrkB-T-Shc include C-terminal sequence variations of 10 and 9 AA, respectively.


NTRK2 gene is preferentially expressed in brain, spinal cord, cranial and spinal ganglia. Expression is most prominent in the following brain regions: amygdale, caudate nucleus, cerebellum, choroid plexus, corpus callosum, cortex, hippocampus, hypothalamus and thalamus. In addition, a variety of cranial structures such as eyes, ophthalmic nerves, various facial districts and vestibular system indicate significant expression. Lower expression is described in several other tissues such as heart, kidney, lung, ovaries, pancreas, pituitary gland, prostate, salivary glands, skeletal muscle, spleen, thymus and thyroid.
Isoforms TrkB and TrkB-T1 are expressed in brain as well as in several peripheral areas, whereas TrkB-T-Shc is primarily expressed in brain.
AceView (NCBI) analysis of cDNA clones supports the expression pattern suggested by the evaluation of mRNA described above. In addition suggests elevated expression in several tumor tissues.


Neuronal activity promotes TrkB translocation from intracellular vesicles to the plasma membrane where it becomes available for neurotrophins. The N-terminal segment is extracellular and is involved in neurotrophin binding and cell adhesion. A single transmembrane segment is located in the central portion of the polypeptide. The C-terminal segment is intracellular and comprises the protein kinase domain.


TrkB specifically binds brain-derived neurotrophic factor (BDNF) and neurotrophin 4/5. It can also bind neurotrophin-3 with low affinity but it excludes nerve growth factor (NGF). Neurotrophin binding triggers receptor dimerization and consequent trans-phosphorylation of tyrosine residues of the TyrKc domain. Phosphorylated receptor undergoes conformational changes, which promote the recruitment of intracellular substrates such SHC1, PI-3 kinase, and PLC-gamma-1. The signaling cascades consequently activated support neuronal survival during development and following injuries, promote neuronal differentiation and maintenance, control short-term and long-term synaptic activity. TrkB can also form heterodimers with the pan-neurotrophin receptor p75NTR or with truncated TrkB. This influences the establishment of specific connections with signaling pathways.


TrkB belongs to the large family of protein kinase comprising a conserved kinase domain. It is included in the subfamily of tyrosine protein kinase. For the presence of a highly conserved intracellular TyrKc domain it is most related to growth factor receptors, and particularly to the neurotrophic factor receptors TrkA and TrkC. The homology with tyrosine kinase receptors is extended to the IGC-2 and LRRs domains, however, these are also present in cell-adhesion molecules.



Heterozygous missense mutations leading to substitution of highly conserved residues have been linked to Obesity, Hyperphagia and Developmental Delay.
Recurrent SNPs of the NTRK2 locus are associated with Eating Disorders (Anorexia and Bulimia nervosa).


Tumor-specific mutations in the kinase domain have been identified in Colorectal Cancer cells.

Implicated in

Entity name
Various diseases
Obesity, Hyperphagia and Developmental Delay. Neuroblastomas, Pancreatic Ductal Adenocarcinomas, Wilmss tumors, Colorectal Cancer.
Overexpression of full-length TrkB is generally associated with malignant transformation. Excessive TrkB signaling through MAPK, PI3K and mTOR pathways support tumor development and metastasis. In highly malignant tumors the overexpression of TrkB enhances angiogenesis and invasive potential by upregulating VEGF and matrix proteases. Furthermore TrkB overcomes apoptosis caused by loss of cell-matrix interactions (anoikis), which is a natural barrier to metastasis.
In contrast with the oncogenic activity of TrkB, the truncated isoforms TrkB-T1 and TrkB-T-Shc, lacking the tyrosine kinase domain, behave as dominant-negative inhibitors and counteract tumor growth.


Atlas Image


Pubmed IDLast YearTitleAuthors
111669152001Human neuroblastomas with unfavorable biologies express high levels of brain-derived neurotrophic factor mRNA and a variety of its variants.Aoyama M et al
127388542003Mutational analysis of the tyrosine kinome in colorectal cancers.Bardelli A et al
153297232004Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB.Douma S et al
176166792007Critical role for TrkB kinase function in anoikis suppression, tumorigenesis, and metastasis.Geiger TR et al
170080232007Neurotrophic receptor TrkB: Is it a predictor of poor prognosis for carcinoma patients?Han L et al
160516412005The neurotrophin receptor TrkB cooperates with c-Met in enhancing neuroblastoma invasiveness.Hecht M et al
25551721989trkB, a novel tyrosine protein kinase receptor expressed during mouse neural development.Klein R et al
81065271994Identification of TrkB autophosphorylation sites and evidence that phospholipase C-gamma 1 is a substrate of the TrkB receptor.Middlemas DS et al
77899881995Cloning and chromosomal localization of the human TRK-B tyrosine kinase receptor gene (NTRK2).Nakagawara A et al
166187482006Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells.Nakamura K et al
157217442005p75NTR--live or let die.Nykjaer A et al
158385342005Contribution of NTRK2 to the genetic susceptibility to anorexia nervosa, harm avoidance and minimum body mass index.Ribases M et al
16563631991A novel modular mosaic of cell adhesion motifs in the extracellular domains of the neurogenic trk and trkB tyrosine kinase receptors.Schneider R et al
157018262005Overexpression of tropomysin-related kinase B in metastatic human pancreatic cancer cells.Sclabas GM et al
16456201991The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor.Soppet D et al
17101741991trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor.Squinto SP et al
117981822002Analysis of the human TrkB gene genomic organization reveals novel TrkB isoforms, unusual gene length, and splicing mechanism.Stoilov P et al
160156472005Delineation of the minimal commonly deleted segment and identification of candidate tumor-suppressor genes in del(9q) acute myeloid leukemia.Sweetser DA et al
21588591990Signal transduction by receptors with tyrosine kinase activity.Ullrich A et al
154947312004A de novo mutation affecting human TrkB associated with severe obesity and developmental delay.Yeo GS et al

Other Information

Locus ID:

NCBI: 4915
MIM: 600456
HGNC: 8032
Ensembl: ENSG00000148053


dbSNP: 4915
ClinVar: 4915
TCGA: ENSG00000148053


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
MAPK signaling pathwayKEGGhsa04010
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
Signal TransductionREACTOMER-HSA-162582
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Activation of TRKA receptorsREACTOMER-HSA-187015
NGF-independant TRKA activationREACTOMER-HSA-187024

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA166182733larotrectinib sulfateChemicalLabelAnnotationassociated
PA444460Heroin DependenceDiseaseClinicalAnnotationassociatedPD23651024
PA445043Opioid-Related DisordersDiseaseClinicalAnnotationassociatedPD23651024
PA447199Bipolar DisorderDiseaseClinicalAnnotationassociatedPD21047205
PA447321Depressive Disorder, MajorDiseaseClinicalAnnotation, VariantAnnotationambiguousPD27378793, 28244805
PA450243lithiumChemicalClinicalAnnotation, Literature, MultilinkAnnotationassociatedPD21047205, 24885933
PA452229antidepressantsChemicalClinicalAnnotation, VariantAnnotationambiguousPD27378793, 28244805


Pubmed IDYearTitleCitations
199271492009TrkB signalling pathways in LTP and learning.283
129127642003Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects.218
194880442009Genome-wide association study of bipolar disorder in European American and African American individuals.162
154947312004A de novo mutation affecting human TrkB associated with severe obesity and developmental delay.147
127196542003Brain-derived neurotrophic factor/TrkB signaling in memory processes.123
156474802005Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia.122
212236462011Decreased BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders.100
198745742009Genetical genomic determinants of alcohol consumption in rats and humans.93
195982352009Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome.92
194170272009Trk receptor expression and inhibition in neuroblastomas.88


Nadia Gabellini

NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2)

Atlas Genet Cytogenet Oncol Haematol. 2007-12-01

Online version: http://atlasgeneticsoncology.org/gene/41589/ntrk2-(neurotrophic-tyrosine-kinase-receptor-type-2)