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.