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Molecular mechanism of Activin receptor inhibition by DLK1

Author

Listed:
  • Daniel Antfolk

    (Moffitt Cancer Center & Research Institute)

  • Qianqian Ming

    (Moffitt Cancer Center & Research Institute)

  • Anna Manturova

    (Moffitt Cancer Center & Research Institute)

  • Erich J. Goebel

    (University of Cincinnati)

  • Thomas B. Thompson

    (University of Cincinnati)

  • Vincent C. Luca

    (Moffitt Cancer Center & Research Institute)

Abstract

Delta-like non-canonical Notch ligand 1 (DLK1) influences myogenesis, adipogenesis, and other aspects of human development through a process that is largely attributed to the downregulation of Notch signaling. Here, we show that DLK1 does not bind to Notch receptors or affect ligand-mediated Notch activation, but instead engages the TGF-β superfamily member Activin receptor type 2B (ACVR2B). The crystal structure of the DLK1-ACVR2B complex reveals that DLK1 mimics the binding mode of canonical TGF-β ligands to compete for access to ACVR2B. In functional assays, DLK1 antagonizes Myostatin-ACVR2B signaling to promote myoblast differentiation, rationalizing a mechanism for the role of DLK1 in muscle development and regeneration. Crosstalk between Notch and TGF-β is mediated by interactions between the transcriptional regulators SMAD2/3 and the Notch intracellular domain (NICD), and DLK1 inhibits SMAD2/3-NICD colocalization. These findings indicate that DLK1 acts directly on ACVR2B to inhibit signaling, whereas the observed effects on Notch may be an indirect result of DLK1 interference with NICD-SMAD complex formation.

Suggested Citation

  • Daniel Antfolk & Qianqian Ming & Anna Manturova & Erich J. Goebel & Thomas B. Thompson & Vincent C. Luca, 2025. "Molecular mechanism of Activin receptor inhibition by DLK1," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60634-3
    DOI: 10.1038/s41467-025-60634-3
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    1. Tomas Malinauskas & Gareth Moore & Amalie F. Rudolf & Holly Eggington & Hayley L. Belnoue-Davis & Kamel El Omari & Samuel C. Griffiths & Rachel E. Woolley & Ramona Duman & Armin Wagner & Simon J. Leed, 2024. "Molecular mechanism of BMP signal control by Twisted gastrulation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
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