NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2)

	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).
Description	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.
Transcription	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).
Pseudogene	None

Note	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).
	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.
Description	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.
Expression	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.
Localisation	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.
Function	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.
Homology	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.

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