Fleming, R.J., Hori, K., Sen, A., Filloramo, G.V., Langer, J.M., Obar, R.A., Artavanis-Tsakonas, S., Maharaj-Best, A.C. (2013). An extracellular region of Serrate is essential for ligand-induced cis-inhibition of Notch signaling.  Development 140(9): 2039--2049.

FBrf0221264

Research paper

Cell-to-cell communication via the Notch pathway is mediated between the membrane-bound Notch receptor and either of its canonical membrane-bound ligands Delta or Serrate. Notch ligands mediate receptor transactivation between cells and also mediate receptor cis-inhibition when Notch and ligand are co-expressed on the same cell. We demonstrate in Drosophila that removal of any of the EGF-like repeats (ELRs) 4, 5 or 6 results in a Serrate molecule capable of transactivating Notch but exhibiting little or no Notch cis-inhibition capacity. These forms of Serrate require Epsin (Liquid facets) to transduce a signal, suggesting that ELR 4-6-deficient ligands still require endocytosis for Notch activation. We also demonstrate that ELRs 4-6 are responsible for the dominant-negative effects of Serrate ligand forms that lack the intracellular domain and are therefore incapable of endocytosis in the ligand-expressing cell. We find that ELRs 4-6 of Serrate are conserved across species but do not appear to be conserved in Delta homologs.

PMC3631976 (PMC) (EuropePMC)