Skip to main content
. Author manuscript; available in PMC: 2021 Feb 10.
Published in final edited form as: J Med Chem. 2018 Sep 19;62(4):1731–1760. doi: 10.1021/acs.jmedchem.8b01092

Figure 2.

Figure 2.

Ligand-independent signaling leading to constitutive TRK activation can occur through three distinct mechanisms: a genomic rearrangement event, extracellular point mutations, or truncations of the extracellular domain. (1) In a genomic rearrangement event, the kinase domain of TRK is fused to an unrelated protein, typically called the fusion partner. In this example, a cytoplasmic chimeric TRK fusion is shown without the transmembrane (TM) domain. Of note, TRK fusions can occur with or without the TM domain.102 (2) Point mutations can occur in the extracellular domain of TRK, generating a TRK oncogene with transforming abilities. Point mutations that are transformative under laboratory conditions have been identified at P203A and C345S.103,104 (3) Through in-frame deletions and alternative splicing events, the TRK kinase can present with a truncated extracellular domain. These aberrant gene products have been identified in AML and neuroblastoma.105–107 FP, fusion partner; KD, kinase domain.