Post Willem Berend, Groß Victoria Elisabeth, Matúš Daniel, Charnay Iannis, Liessmann Fabian, Seufert Florian, Hildebrand Peter, Meiler Jens, Kaiser Anette, Schöneberg Torsten, Prömel Simone
Institute of Cell Biology, Department of Biology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, Leipzig, Germany.
Nat Commun. 2025 Jul 12;16(1):6461. doi: 10.1038/s41467-025-61730-0.
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.
Notch信号通路是后生动物中高度保守的信号级联反应，可调节众多生理过程，包括细胞增殖、分化和命运决定。鉴于其重要作用，该信号通路受到多种分子通过多种机制的严格调控。在此，我们确定粘附G蛋白偶联受体促胃液素释放肽受体（LPHN/ADGRL）为Notch信号的正向调节剂，它可增加Notch受体的激活及其胞内结构域向细胞核的转位。在生理上，这种促胃液素释放肽受体的作用对于平衡线虫秀丽隐杆线虫性腺干细胞微环境中增殖细胞的数量至关重要。计算机模拟、体外和体内分析表明，秀丽隐杆线虫促胃液素释放肽受体同源物LAT-1与同一细胞上的DSL蛋白/Notch配体LAG-2直接相互作用。这种相互作用由LAT-1保守的GAIN和RBL结构域介导。重要的是，调节作用仅取决于受体的N末端，且独立于G蛋白信号传导。最后，我们探讨了aGPCR对Notch信号进行这种微调的意义。
