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Phase separation underlies signaling activation of oncogenic NTRK fusions

Tianxin Zhu1,2, Jingjing Xie3, Hao He3

  • 1Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China.

Proceedings of the National Academy of Sciences of the United States of America
|October 9, 2023
PubMed

Insights

NTRK gene fusions create oncogenic proteins that form liquid-like condensates. These condensates, driven by fusion partners, concentrate signaling complexes, accelerating cancer development.

Area of Science:

  • Molecular oncology
  • Biochemistry
  • Cell biology

Background:

  • NTRK gene fusions are key drivers in various cancers, leading to constitutively active TRK proteins.
  • The precise oncogenic mechanisms of NTRK fusions, particularly involving diverse N-terminal partners, are not fully understood.

Purpose of the Study:

  • To elucidate the underlying mechanisms of oncogenesis driven by NTRK gene fusions.
  • To investigate the role of N-terminal fusion partners in NTRK-mediated oncogenic signaling.

Main Methods:

  • Analysis of NTRK fusion protein behavior in cellular models.
  • Investigation of condensate formation and its impact on kinase activity and downstream signaling.

Main Results:

  • NTRK fusion proteins self-assemble into liquid-like condensates, driven by their N-terminal partners.
  • These condensates enhance kinase reactions and concentrate downstream signaling complexes.
  • Phase separation is critical for TRK activation and oncogenic signaling.

Conclusions:

  • Phase separation is a key mechanism by which NTRK fusions drive oncogenesis.
  • NTRK-driven condensates act as hubs for oncogenic signaling pathways.
  • Targeting these condensates could offer novel therapeutic strategies for NTRK-fusion-positive cancers.
Keywords:
NTRKfusion oncoproteinskinase activationliquid–liquid phase separation

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