NTRK fusions discussed on this website

NTRK Fusion genes and their proteins

5’Partner-3’NTRK  fusion genes are translated into fusion proteins with an N-terminal from the fusion partner and the kinase domain of Trk at the C-terminal.

  • Most of the Trk fusion partners are moderately to highly abundant “housekeeping” proteins.
  • All of the Trk fusion partners form dimers or even oligomers.  Growth factor independent, constantly active kinases are likely.

Some basic kinase biochemistry has been covered on another page.

TPM3-NTRK1  is a fusion between the cytoskeletal protein tropomyosin and TrkA.

  • Cytoskeletal proteins such as tropomyosin are some of the most abundant proteins in the cell.
  • If the tropomyosin-TrkA fusion can still bind filamentous actin, we can anticipate the kinase domains would be in close enough proximity for autophosphorylation to occur.

BCAN-NTRK1  is a fusion between extracellular matrix protein brevican and TrkA.

  • Brevican is a moderately abundant housekeeping protein that links polysaccharides in the extracellular matrix.
  • TrkA kinase domains could conceivably be brought together close enough for autophosphorylation by the fusion binding intracellular polysaccharides.

LMNA-NTRK1 is a fusion between the nuclear matrix protein laminin A/C and the kinase domain of TrkA.

  • Laminin A/C are abundant proteins that form structural polymers in the nucleus.
  • The polymerization domains of laminin remain in the laminin-TrkA fusion.  It is highly conceivable that truncated laminin can polymerize and bring TrkA kinase domains in close enough proximity for autophosphorylation to occur.

NFASC-NTRK1 is a fusion between neurofascin and TrkA

  • Neurofascin is an abundant cytoskeletal protein of neurons that facilitates neurite outgrowth.
  • Neurofascin polymerization domains are left intact in the fusion protein.   TrkA autophosphorylation is highly conceivable.

SQSTM1-NTRK1 is a fusion between the scaffold protein  p62 (a.k.a sequestosome 1) and TrkA

  •  p62 is a scaffold protein involved in protein turnover and signaling. and  It is commonly found in dense protein bodies in eukaryotic cells.
  • The domains responsible for formation of p62 filaments remain in the fusion protein.  Again, it is highly conceivable that TrkA kinase domains will be in close enough proximity for autophosphorylation in p62-TrkA filaments.

QKI-NTRK2 is a fusion between “protein quaking” and NTRK2.

  • Protein quaking is a moderately abundant mRNA binding protein that regulates transcript translation into protein.
  • Protein quaking only forms dimers, and as far as we know, not filaments.  The dimerization domain is intact in the fusion.  The TrkB kinase domains are anticipated be active kinases in the fusion.

ETV6-NTRK3 is a fusion between the multi-functional transcription factor TEL and the kinase domain of TrkC.

  • TEL has two domains:  one for dimerization/polymerization, the other for DNA binding.
  • The DNA binding domain of TEL is lost in the fusion.  The remaining polymerization domain has been demonstrated to form filaments with the active TrkC kinase domain in the fusion.

Trk family kinase domain diversity considerations

Most of our posts concentrate on features of the Trk fusion partners that facilitate activation in the absence of dimerization inducing growth factors.

Trk family kinase domain diversity as seen in UniProt. NTRK fusion Specific interaction domains are seen in Blue box

Trk kinase domains from UniProt

The interaction domains in the blue boxes deserve some special note

  • SHC (Src Homology 2 Domain Containing) Transforming Protein 1.  SH2 domains recognize phosphorylated tyrosine motifs and are commonly found in adapter proteins in signal transduction cascades.
  • SH2D1A (SH2 Domain Containing 1A ) is another adapter protein involved in immune and Trk signaling.
  • PLCg1 (phospholipase Cϒ1) catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate.
  • SQSTM1 (Sequestosome-1, a.k.a. the  ubiquitin-binding protein p62) has dual roles of a facilitator of phagocytosis and as an an adapter protein in insulin signaling. It is also found in a fusion protein with one of the Trks, SQSTM1-NTRK1.

How do the fusion partners influence binding of Trk substrates?  Does the Trk isoform matter?

 Important Information

The discovery of each new NTRK gene fusion is a learning experience about the protein domains in the translated fusion protein.  The Murphy Method is an clever, inexpensive method to detect cancer driving NTRK gene fusions.

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.