Regulated proteolysis of NOTCH2 and NOTCH3 receptors by ADAM10 and presenilins.
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 γ-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 γ-secretase complex, leading to transcriptional activation.
Department of Radiotherapy (MAASTRO)/GROW-School for Developmental Biology & Oncology, Maastricht University, Maastricht, Netherlands.
Arjan J
AJ
Groot
Department of Radiotherapy (MAASTRO)/GROW-School for Developmental Biology & Oncology, Maastricht University, Maastricht, Netherlands.
Roger
R
Habets
Department of Radiotherapy (MAASTRO)/GROW-School for Developmental Biology & Oncology, Maastricht University, Maastricht, Netherlands.
Sanaz
S
Yahyanejad
Department of Radiotherapy (MAASTRO)/GROW-School for Developmental Biology & Oncology, Maastricht University, Maastricht, Netherlands.
Caroline M
CM
Hodin
Department of Dermatology and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Karina
K
Reiss
Institute of Biochemistry, University of Kiel, Kiel, Germany.
Paul
P
Saftig
Department of Radiotherapy (MAASTRO)/GROW-School for Developmental Biology & Oncology, Maastricht University, Maastricht, Netherlands.
Jan
J
Theys
Department of Radiotherapy (MAASTRO)/GROW-School for Developmental Biology & Oncology, Maastricht University, Maastricht, Netherlands marc.vooijs@maastrichtuniversity.nl.
Marc
M
Vooijs
D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D053764:Presenilin-1 / Q000378:metabolism*; D053766:Presenilin-2 / Q000378:metabolism*; D059748:Proteolysis; D051883:Receptor, Notch2 / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*
D008565:Membrane Proteins; D053764:Presenilin-1; D053766:Presenilin-2; D051883:Receptor, Notch2; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D045726:Metalloproteases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse