Tropomyosin receptor kinase B

Tropomyosin receptor kinase B (TrkB), also known as Tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the NTRK2 gene. TrkB is a receptor for brain-derived neurotrophic factor (BDNF).

Function

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 (Brain Derived Neurotrophic Factor), neurotrophin-4 (NT-4), and neurotrophin-3 (NT-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 (or VEGF) receptor, etc.

TrkB signaling

Currently, there are three TrkB isoforms in the mammalian CNS. The full-length isoform (TK+) is a typical tyrosine kinase receptor, and transduces the BDNF signal via Ras-ERK, PI3K, and PLCγ. In contrast, two truncated isoforms (TK-: T1 and T2) 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 (11 and 9 amino acids, respectively). 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 TrkA and TrkC. Also, there are other neurotrophic factors structurally related to BDNF: NGF (for Nerve Growth Factor), NT-3 (for Neurotrophin-3) and NT-4 (for Neurotrophin-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" (for "low-affinity nerve growth factor receptor"). As opposed to 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.

Interactions

TrkB has been shown to interact with:

• Brain-derived neurotrophic factor (BDNF),
• FYN,
• NCK2,
• PLCG1,
• Sequestosome 1, and
• SHC3.

Ligands

Agonists

• 3,7-Dihydroxyflavone
• 3,7,8,2'-Tetrahydroxyflavone
• 4'-Dimethylamino-7,8-dihydroxyflavone
• 7,3′-Dihydroxyflavone
• 7,8-Dihydroxyflavone
• 7,8,2'-Trihydroxyflavone
• 7,8,3'-Trihydroxyflavone
• Amitriptyline
• Brain-derived neurotrophic factor (BDNF)
• Deoxygedunin
• Diosmetin
• HIOC
• LM22A-4
• N-Acetylserotonin
• Neurotrophin-3 (NT-3)
• Neurotrophin-4 (NT-4)
• Norwogonin (5,7,8-THF)
• R7
• TDP6

Antagonists

• ANA-12
• Cyclotraxin B
• Gossypetin (3,5,7,8,3',4'-HHF)

See also

• Trk receptor

External links

• Memories are made of this molecule - New Scientist, 15 January 2007.