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<p>The Notch pathway is a highly conserved signaling cascade across metazoans that regulates numerous physiological processes, including cell proliferation, differentiation, and fate determination. Given its fundamental roles, the pathway is tightly regulated by diverse molecules through multiple mechanisms. Here, we identify the Adhesion GPCR latrophilin (LPHN/ADGRL) as a positive modulator of Notch signaling, which increases Notch receptor activation and the translocation of its intracellular domain into the nucleus. Physiologically, this latrophilin role is crucial for balancing the number of proliferating cells in the gonadal stem cell niche of the nematode <i>C. elegans</i>. In silico, in vitro, and in vivo analyses demonstrate that the <i>C. elegans</i> latrophilin homolog LAT-1 directly interacts with the DSL protein/Notch ligand LAG-2 on the same cell. This interaction is mediated by LAT-1’s conserved GAIN and the RBL domain. Importantly, the modulatory effect depends solely on the receptor’s N terminus and is&#xa0;independent of G protein signaling. Finally, we explore the implications of this fine-tuning of Notch signaling by an aGPCR.</p>

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Notch activity is modulated by the aGPCR Latrophilin binding the DSL ligand in C. elegans

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月12日

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  • Willem Berend Post,
  • Victoria Elisabeth Groß,
  • Daniel Matúš,
  • Iannis Charnay,
  • Fabian Liessmann,
  • Florian Seufert,
  • Peter Hildebrand,
  • Jens Meiler,
  • Anette Kaiser,
  • Torsten Schöneberg,
  • Simone Prömel

摘要

The Notch pathway is a highly conserved signaling cascade across metazoans that regulates numerous physiological processes, including cell proliferation, differentiation, and fate determination. Given its fundamental roles, the pathway is tightly regulated by diverse molecules through multiple mechanisms. Here, we identify the Adhesion GPCR latrophilin (LPHN/ADGRL) as a positive modulator of Notch signaling, which increases Notch receptor activation and the translocation of its intracellular domain into the nucleus. Physiologically, this latrophilin role is crucial for balancing the number of proliferating cells in the gonadal stem cell niche of the nematode C. elegans. In silico, in vitro, and in vivo analyses demonstrate that the C. elegans latrophilin homolog LAT-1 directly interacts with the DSL protein/Notch ligand LAG-2 on the same cell. This interaction is mediated by LAT-1’s conserved GAIN and the RBL domain. Importantly, the modulatory effect depends solely on the receptor’s N terminus and is independent of G protein signaling. Finally, we explore the implications of this fine-tuning of Notch signaling by an aGPCR.