Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Sci Signal. 2015 Mar 24;8(369):ra30. doi: 10.1126/scisignal.2005892.

Site-specific methylation of Notch1 controls the amplitude and duration of the Notch1 response.

Author information

1
Max-Planck-Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany. Institute of Biochemistry, University of Giessen, 35392 Giessen, Germany.
2
Max-Planck-Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany. BIOSS, Center for Biological Signalling Studies, University of Freiburg, Schänzlestrasse 18, 79104 Freiburg, Germany.
3
Institute for Biochemistry and Molecular Biology, Ulm University, 89081 Ulm, Germany.
4
Institute of Biochemistry, University of Giessen, 35392 Giessen, Germany.
5
Department of Cell Biology, Harvard Medical School and Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02215, USA.
6
Department of Internal Medicine II, Center for Internal Medicine, University Medical Center Ulm, 89081 Ulm, Germany.
7
Core Unit Medical Systems Biology, Institute of Neural Information Processing, Ulm University, 89069 Ulm, Germany.
8
Core Unit Medical Systems Biology, Institute of Neural Information Processing, Ulm University, 89069 Ulm, Germany. Friedrich-Schiller University and Fritz Lipmann Institute, Leibniz Institute for Aging Research, D-07745 Jena, Germany.
9
Department of Internal Medicine I, Center for Internal Medicine, University Medical Center Ulm, 89081 Ulm, Germany. tilman.borggrefe@biochemie.med.uni-giessen.de franz.oswald@uni-ulm.de.
10
Max-Planck-Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany. Institute of Biochemistry, University of Giessen, 35392 Giessen, Germany. tilman.borggrefe@biochemie.med.uni-giessen.de franz.oswald@uni-ulm.de.

Abstract

Physiologically, Notch signal transduction plays a pivotal role in differentiation; pathologically, Notch signaling contributes to the development of cancer. Transcriptional activation of Notch target genes involves cleavage of the Notch receptor in response to ligand binding, production of the Notch intracellular domain (NICD), and NICD migration into the nucleus and assembly of a coactivator complex. Posttranslational modifications of the NICD are important for its transcriptional activity and protein turnover. Deregulation of Notch signaling and stabilizing mutations of Notch1 have been linked to leukemia development. We found that the methyltransferase CARM1 (coactivator-associated arginine methyltransferase 1; also known as PRMT4) methylated NICD at five conserved arginine residues within the C-terminal transactivation domain. CARM1 physically and functionally interacted with the NICD-coactivator complex and was found at gene enhancers in a Notch-dependent manner. Although a methylation-defective NICD mutant was biochemically more stable, this mutant was biologically less active as measured with Notch assays in embryos of Xenopus laevis and Danio rerio. Mathematical modeling indicated that full but short and transient Notch signaling required methylation of NICD.

PMID:
25805888
DOI:
10.1126/scisignal.2005892
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center