Tropomyosin receptor kinase B is the high affinity catalytic receptor for several "neurotrophins", which are small protein growth factors that induce the survival and differentiation of distinct cell populations. The neurotrophins that activate TrkB are: BDNF, neurotrophin-4, and neurotrophin-3. As such, TrkB mediates the multiple effects of these neurotrophic factors, which includes neuronal differentiation and survival. Research has shown that activation of the TrkB receptor can lead to down regulation of the KCC2 chloride transporter in cells of the CNS. The TrkB receptor is part of the large family of receptor tyrosine kinases. A "tyrosine kinase" is an enzyme which is capable of adding a phosphate group to certain tyrosines on target proteins, or "substrates". A receptor tyrosine kinase is a "tyrosine kinase" which is located at the cellular membrane, and is activated by binding of a ligand to the receptor's extracellular domain. Other examples of tyrosine kinase receptors include the insulin receptor, the IGF1 receptor, the MuSK protein receptor, the Vascular Endothelial Growth Factor receptor, etc. Currently, there are three TrkB isoforms in the mammalian CNS. The full-length isoform is a typical tyrosine kinase receptor, and transduces the BDNF signal via Ras-ERK, PI3K, and PLCγ. In contrast, two truncated isoforms possess the same extracellular domain, transmembrane domain, and first 12 intracellular amino acid sequences as TK+. However, the C-terminal sequences are the isoform-specific. T1 has the original signaling cascade that is involved in the regulation of cell morphology and calcium influx.
Family members
TrkB is part of a sub-family of protein kinases which includes Papa TrkB, Mama TrkB, Baby TrkB, and also TrkA and TrkC. Also, there are other neurotrophic factors structurally related to BDNF: NGF, NT-3 and NT-4. While TrkB mediates the effects of BDNF, NT-4 and NT-3, TrkA is bound and thereby activated only by NGF. Further, TrkC binds and is activated by NT-3. TrkB binds BDNF and NT-4 more strongly than it binds NT-3. TrkC binds NT-3 more strongly than TrkB does.
LNGFR
There is one other BDNF receptor besides TrkB, called the "LNGFR". Unlike TrkB, the LNGFR plays a somewhat less clear role in BDNF biology. Some researchers have shown the LNGFR binds and serves as a "sink" for neurotrophins. Cells which express both the LNGFR and the Trk receptors might therefore have a greater activity – since they have a higher "microconcentration" of the neurotrophin. It has also been shown, however, that the LNGFR may signal a cell to die via apoptosis – so therefore cells expressing the LNGFR in the absence of Trk receptors may die rather than live in the presence of a neurotrophin.
Role in cancer
Although originally identified as an oncogenic fusion in 1982, only recently has there been a renewed interest in the Trk family as it relates to its role in human cancers because of the identification of NTRK1, NTRK2 and NTRK3 gene fusions and other oncogenic alterations in a number of tumor types. A number of Trk inhibitors are in clinical trials and have shown early promise in shrinking human tumors.
