Regulated Proteolysis of NOTCH2 and NOTCH3 Receptors by ADAM10 and Presenilins

Arjan J. Groot, Roger Habets, Sanaz Yahyanejad, Caroline M. Hodin, Karina Reiss, Paul Saftig, Jan Theys, Marc Vooijs*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


In mammals, there are four NOTCH receptors and five Delta-Jagged-type ligands regulating many aspects of embryonic development and adult tissue homeostasis. NOTCH proteins are type I transmembrane receptors that interact with ligands on adjacent cells and are activated by regulated intramembrane proteolysis (RIP). The activation mechanism of NOTCH1 receptors upon ligand binding is well understood and requires cleavage by ADAM10 metalloproteases prior to intramembranous cleavage by gamma-secretase. How the other human NOTCH receptor homologues are activated upon ligand binding is not known. Here, we dissect the proteolytic activation mechanism of the NOTCH2 and NOTCH3 receptors. We show that NOTCH2 and NOTCH3 signaling can be triggered by both Delta-Jagged-type ligands and requires ADAM10 and presenilin-1 or -2. Importantly, we did not find any role for the highly related ADAM17/TACE (tumor necrosis factor alpha-converting enzyme) protease in ligand-induced NOTCH2 or NOTCH3 signaling. These results demonstrate that canonical ligand-induced proteolysis of the NOTCH1, -2, and -3 receptors strictly depends on consecutive cleavage of these receptors by ADAM10 and the presenilin-containing gamma-secretase complex, leading to transcriptional activation.
Original languageEnglish
Pages (from-to)2822-2832
JournalMolecular and Cellular Biology
Issue number15
Publication statusPublished - Aug 2014

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