The Neurotrophic tyrosine kinase (NTRK) Gene Family

What are NTRK (1/2/3)?

Neurotrophic tyrosine kinase (NTRK) is the name of the family of three genes encoding tropmomyosin receptor kinases (Trk) A, B, and C.

Tropomyosin receptor kinases belong to a larger group of receptor tyrosine kinases.

  • Receptor tyrosine kinases exist as monomers in the absence of extracellular ligands, usually growth factors.
  • When ligands bind, two kinases dimerize.
  • Dimerization causes auto- or transphosphorylation.
  • When the kinase is phosphorylated, it then is able to phosphorylate other enzymes activated by phosphorylation.
Cartoon of tyrosine kinase embeded in plasma membrane showing extra and intra cellular location. Growth factor binding at the extra cellular domain leads to transphosphorylation and activation on intra cellular domain.

Figure 1. Kinases transfer a the high energy ϒ-phosphate from ATP to the hydroxyl group of tyrosine, serine, or threonine side chains of proteins.  The introduction of the phosphate group serves to activate the protein, usually an enzyme (courtesy Garland Science).

 

Cartoon showing how inactive enzymes tyrosine side chain gets activated by tranfer of an phosphate group

Figure 2. Protein phosphorylation is the transfer of a phosphate from ATP to the hydroxyl group of an amino acid side chain.

The three Trk family members have slightly different receptor selectivity the family of neurotrophins.

  • Nerve growth factor (NGF).
  • Brain-derived neurotrophic factor (BDNF)is a member of the neurotrophin family of growth factors, which are related to Nerve Growth Factor.
  • Neurotrophin 4 (NT-4) is also known as NT-5.
  • Neurotrophin 3 (NT-3).
Cartoon showing trk protein family members embedded in membrane with extracellular and intracellular binding domains

Figure 3. Trk family members.

 

Flow diagram showing neurotrophin led activation, autophosphorylation and activation of 3 signaling cascades

Figure 4. The three down stream targets of activated Trk.

The three pathways activated by Trk result in neuronal cell survival, angiogenesis, proliferation, and invasion.

Cartoon of trk activation leading to 3 pathways leading to cell proliferation, survival, invasion and angiogenesis

Figure 5. The end result of Trk activation.

When viewing Figure 5 it should be remembered that Trk are not abundant proteins and are under control of growth factors.  It should be emphasized that transcription from the fusion gene is under the control of the fusion gene’s promoter/enhancer region.    These are often house keeping genes expressed continuously and in large amounts.  They have different transcription factor binding sites in their promoters to adjust for a greater need of the proteins which the genes code.

figure showing NTRK1, 2 and 3 with their housekeeping fusion partners

Figure 6. Transcription factors of NTRK and select fusion partner genes (from Genecards).

In our post section we have reviewed the TPM3:NTRK1, ETV6:NTRK3, and more of these gene products can form dimers and multimers when fused to Trk kinase domains.

The chromosomal location of these three closely related genes are given in Figure 7 below. Some regions of our chromosomes contain fragile sites that are prone to breakage. The availability of these genes for fusion events might also depend whether other genes in the region are being transcribed into mRNA to be translated into proteins by the ribosomes.

The GeneCards.org location of the three NTRK genes by chromosome

Figure 7. The GeneCards.org location of the three NTRK genes by chromosome

 Important information

The effectiveness of a small molecule Trk  inhibitor on the three pathways discussed on this page has been tested in a TrkB over expressing cell line grown as xenograph tumors in nude mice.  There is an open TRK fusion clinical trial that is actively enrolling any solid tumor patient with NTRK fusions (STARTRK-2).   For more information go to the NTRK trial website.