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Development 140 (9): 2039-2049


An extracellular region of Serrate is essential for ligand-induced cis-inhibition of Notch signaling

Robert J. Fleming1,*, Kazuya Hori2, Anindya Sen2, Gina V. Filloramo1, Jillian M. Langer1, Robert A. Obar2, Spyros Artavanis-Tsakonas2,*, and Ayiti C. Maharaj-Best1

1 Trinity College, Department of Biology, 300 Summit Street, Hartford, CT 06106, USA.
2 Harvard Medical School, Department of Cell Biology, 240 Longwood Avenue, LHRRB 410, Boston, MA 02115, USA.

* Authors for correspondence (robert.fleming{at}; sartavanis{at}

Accepted for publication 28 February 2013.

Abstract: 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.

Key Words: NotchCis-inhibitionSerrate ligandExtracellular domain

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