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Publications

Journal Article Ppublish

PubMed: 40875402 DOI: 10.1091/mbc.E25-03-0113

Trimerization domain-interfering peptide inhibits EML4-ALK condensate formation, fusion-dependent signaling, and cell growth.

Mol Biol Cell 36(10):br25

Authors: Kyle Scheller, Xin Zhou, Kun Li, Lan Jiang, Rodrigo Ochoa, Pilar Cossio, Lizi Wu, Juan Guan

Affiliations

  • Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610. University of Florida Health Cancer Center, Gainesville, FL 32610.
  • College of Pharmacy, University of Texas at Austin, TX 78712.
  • Biophysics of Tropical Diseases Max Planck Tandem Group, University of Antioquia UdeA, 050010 Medellin, Colombia.
  • Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610.
  • University of Florida Health Cancer Center, Gainesville, FL 32610.
  • University of Florida Genetics Institute, Gainesville, FL 32610.

Abstract

Biomolecular condensates are micrometer-scale subcellular structures assembled through protein phase separation in living cells. Recent research shows that they are critical to normal biological processes and their misregulation may contribute to disease. A prominent example is the cancer-causing EML4-ALK fusion protein, which spontaneously forms biomolecular condensates that significantly enhance receptor tyrosine kinase (RTK) signaling within the condensate microenvironment. In this work, we show that a trimerization domain (TD) in EML4-ALK is necessary for condensate formation. By designing a peptide targeting the TD, we disrupted EML4-ALK self-assembly, leading to the dissolution of pre-existing EML4-ALK condensates in patient lung tumor-derived cells. Notably, this disruption significantly reduced EML4-ALK-dependent signaling and cell proliferation. Our findings demonstrate that interfering with a specific protein-protein interaction can disrupt oncogenic biomolecular condensates and attenuate their associated signaling. These results highlight the potential of targeting condensate assembly as a strategy to modulate oncogenic signaling.

MeSH

Cells, Growth, Molecular Biology, Neoplasms