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Updated: Jun 22, 2025

Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
09:49

Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing

Published on: July 5, 2019

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Critical domains for NACC2-NTRK2 fusion protein activation

Wei Yang1, April N Meyer1, Zian Jiang1

  • 1Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America.

Plos One
|June 27, 2024
PubMed

Insights

The NACC2-NTRK2 fusion protein drives pediatric brain cancers by activating NTRK2 kinase activity through BTB domain multimerization. Inhibiting this BTB domain may offer a new cancer treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Neurotrophic receptor tyrosine kinases (NTRKs) are key regulators of cell signaling, and their aberrant activation through mutations drives oncogenesis.
  • NTRK-associated fusions, such as NACC2-NTRK2, are implicated in pediatric brain tumors like pilocytic astrocytoma and glioblastoma.
  • Understanding the structural and functional domains of these fusion proteins is crucial for developing targeted therapies.

Purpose of the Study:

  • To characterize the oncogenic NACC2-NTRK2 fusion protein, identifying critical domains responsible for its biological activity.
  • To investigate the role of the NACC2 BTB domain in the multimerization and activation of the NTRK2 kinase domain.
  • To explore the therapeutic potential of targeting the BTB domain or other structural features of the fusion protein.

Main Methods:

  • Site-directed mutagenesis was employed to introduce mutations in the NACC2 BTB domain (charged pocket and monomer core) and the NTRK2-derived portion.
  • Structural comparisons with other BTB-containing proteins (e.g., PLZF) guided mutation design.
  • Kinase activity assays and downstream signaling pathway analysis were performed to assess the functional impact of mutations.

Main Results:

  • Activation of the NTRK2 kinase domain in the NACC2-NTRK2 fusion protein is dependent on multimerization mediated by the NACC2 BTB domain.
  • Mutations disrupting BTB domain multimerization significantly reduced kinase activity and downstream signaling.
  • Removal of the transmembrane helix enhanced fusion protein stability and activity, suggesting a role in oncogenicity for specific isoforms.

Conclusions:

  • The NACC2-NTRK2 fusion protein's oncogenic activity relies on BTB domain-mediated multimerization, which activates the NTRK2 kinase.
  • Targeting the BTB domain represents a promising therapeutic strategy for NACC2-NTRK2-driven cancers.
  • Distinct NACC2-NTRK2 isoforms, potentially lacking the transmembrane helix, may contribute to pediatric glioblastoma development.

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