Human NOTCH2 Is Resistant to Ligand-independent Activation by Metalloprotease Adam17 |
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| Authors: | Roger A J Habets Arjan J Groot Sanaz Yahyanejad Kittichoat Tiyanont Stephen C Blacklow Marc Vooijs |
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| Institution: | From the ‡Department of Radiotherapy (MaastRO)/GROW, School for Developmental Biology & Oncology, Maastricht University, 6200 MD Maastricht, The Netherlands.;§Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, and ;¶Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115 |
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| Abstract: | Cell surface receptors of the NOTCH family of proteins are activated by ligand induced intramembrane proteolysis. Unfolding of the extracellular negative regulatory region (NRR), enabling successive proteolysis by the enzymes Adam10 and γ-secretase, is rate-limiting in NOTCH activation. Mutations in the NOTCH1 NRR are associated with ligand-independent activation and frequently found in human T-cell malignancies. In mammals four NOTCH receptors and five Delta/Jagged ligands exist, but mutations in the NRR are only rarely reported for receptors other than NOTCH1. Using biochemical and functional assays, we compared the molecular mechanisms of ligand-independent signaling in NOTCH1 and the highly related NOTCH2 receptor. Both murine Notch1 and Notch2 require the metalloprotease protease Adam17, but not Adam10 during ligand-independent activation. Interestingly, the human NOTCH2 receptor is resistant to ligand-independent activation compared with its human homologs or murine orthologs. Taken together, our data reveal subtle but functionally important differences for the NRR among NOTCH paralogs and homologs. |
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