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

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.

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Journal
Nature Communications
Published
2025-07-12
DOI
https://doi.org/10.1038/s41467-025-61730-0
Citations
2
Primary Topic
Genetics, Aging, and Longevity in Model Organisms
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article
Field-Weighted Citation Impact
1.91

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article

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

Anette Kaiser, Willem Berend Post, Jens Meiler, Victoria Elisabeth Groß et al.
2 citations
Nature Communications
Genetics, Aging, and Longevity in Model Organisms
1.91
article

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

Anette Kaiser, Willem Berend Post, Jens Meiler, Victoria Elisabeth Groß, Daniel Matúš, Simone Prömel, Fabian Ließmann, Torsten Schöneberg, Peter W. Hildebrand, Florian Seufert, Iannis Charnay
article en
2 citations

Abstract

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.

Nature CommunicationsVol. 16(1)
Vanderbilt University (US), University Hospital Leipzig (DE), University of Global Health Equity (RW), Heinrich Heine University Düsseldorf (DE), Leipzig University (DE), Stanford University (US)
Alexander von Humboldt-Stiftung, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Heinrich-Heine-Universität Düsseldorf, Universität Leipzig, National Institutes of Health
Life in Land
Openalex Percentile: Top 15%
Genetics, Aging, and Longevity in Model Organisms
1.91
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