title: Site-specific methylation of Notch1 controls the amplitude and duration of the Notch1 response.
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.
authors: Max-Planck-Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany. Institute of Biochemistry, University of Giessen, 35392 Giessen, Germany.
authors: Kerstin
authors: K
authors: Hein
authors: Max-Planck-Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany. BIOSS, Center for Biological Signalling Studies, University of Freiburg, Schänzlestrasse 18, 79104 Freiburg, Germany.
authors: Gerhard
authors: G
authors: Mittler
authors: Institute for Biochemistry and Molecular Biology, Ulm University, 89081 Ulm, Germany.
authors: Wiebke
authors: W
authors: Cizelsky
authors: Institute for Biochemistry and Molecular Biology, Ulm University, 89081 Ulm, Germany.
authors: Michael
authors: M
authors: Kühl
authors: Institute of Biochemistry, University of Giessen, 35392 Giessen, Germany.
authors: Francesca
authors: F
authors: Ferrante
authors: Department of Cell Biology, Harvard Medical School and Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02215, USA.
authors: Robert
authors: R
authors: Liefke
authors: Department of Internal Medicine II, Center for Internal Medicine, University Medical Center Ulm, 89081 Ulm, Germany.
authors: Ina M
authors: IM
authors: Berger
authors: Department of Internal Medicine II, Center for Internal Medicine, University Medical Center Ulm, 89081 Ulm, Germany.
authors: Steffen
authors: S
authors: Just
authors: Core Unit Medical Systems Biology, Institute of Neural Information Processing, Ulm University, 89069 Ulm, Germany.
authors: J Eric
authors: JE
authors: Sträng
authors: 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.
authors: Hans A
authors: HA
authors: Kestler
authors: 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.
authors: Franz
authors: F
authors: Oswald
authors: 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.
authors: Tilman
authors: T
authors: Borggrefe
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008745:Methylation; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D015533:Transcriptional Activation; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
chemical_list: D051881:Receptor, Notch1; D001120:Arginine; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1