Critical domains for NACC2-NTRK2 fusion protein activation.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Oncogene Proteins, Fusion*/genetics ; Oncogene Proteins, Fusion*/metabolism ; Oncogene Proteins, Fusion*/chemistry; Humans ; Receptor, trkB/metabolism ; Receptor, trkB/genetics ; Protein Domains ; Mutation ; Membrane Glycoproteins/metabolism ; Membrane Glycoproteins/genetics ; Glioblastoma/genetics ; Glioblastoma/metabolism ; Glioblastoma/pathology ; Signal Transduction ; Protein Multimerization

Neurotrophic receptor tyrosine kinases (NTRKs) belong to the receptor tyrosine kinase (RTK) family. NTRKs are responsible for the activation of multiple downstream signaling pathways that regulate cell growth, proliferation, differentiation, and apoptosis. NTRK-associated mutations often result in oncogenesis and lead to aberrant activation of downstream signaling pathways including MAPK, JAK/STAT, and PLCγ1. This study characterizes the NACC2-NTRK2 oncogenic fusion protein that leads to pilocytic astrocytoma and pediatric glioblastoma. This fusion joins the BTB domain (Broad-complex, Tramtrack, and Bric-a-brac) domain of NACC2 (Nucleus Accumbens-associated protein 2) with the transmembrane helix and tyrosine kinase domain of NTRK2. We focus on identifying critical domains for the biological activity of the fusion protein. Mutations were introduced in the charged pocket of the BTB domain or in the monomer core, based on a structural comparison of the NACC2 BTB domain with that of PLZF, another BTB-containing protein. Mutations were also introduced into the NTRK2-derived portion to allow comparison of two different breakpoints that have been clinically reported. We show that activation of the NTRK2 kinase domain relies on multimerization of the BTB domain in NACC2-NTRK2. Mutations which disrupt BTB-mediated multimerization significantly reduce kinase activity and downstream signaling. The ability of these mutations to abrogate biological activity suggests that BTB domain inhibition could be a potential treatment for NACC2-NTRK2-induced cancers. Removal of the transmembrane helix leads to enhanced stability of the fusion protein and increased activity of the NACC2-NTRK2 fusion, suggesting a mechanism for the oncogenicity of a distinct NACC2-NTRK2 isoform observed in pediatric glioblastoma.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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0 (Oncogene Proteins, Fusion)
EC 2.7.10.1 (Receptor, trkB)
EC 2.7.10.1 (tropomyosin-related kinase-B, human)
0 (Membrane Glycoproteins)

Date Created: 20240627 Date Completed: 20240627 Latest Revision: 20240719

20240719

PMC11210774

10.1371/journal.pone.0301730

38935636