title: The Notch intracellular domain integrates signals from Wnt, Hedgehog, TGFβ/BMP and hypoxia pathways.
abstract: Notch signaling is a highly conserved signal transduction pathway that regulates stem cell maintenance and differentiation in several organ systems. Upon activation, the Notch receptor is proteolytically processed, its intracellular domain (NICD) translocates into the nucleus and activates expression of target genes. Output, strength and duration of the signal are tightly regulated by post-translational modifications. Here we review the intracellular post-translational regulation of Notch that fine-tunes the outcome of the Notch response. We also describe how crosstalk with other conserved signaling pathways like the Wnt, Hedgehog, hypoxia and TGFβ/BMP pathways can affect Notch signaling output. This regulation can happen by regulation of ligand, receptor or transcription factor expression, regulation of protein stability of intracellular key components, usage of the same cofactors or coregulation of the same key target genes. Since carcinogenesis is often dependent on at least two of these pathways, a better understanding of their molecular crosstalk is pivotal.
authors.affiliation: Institute of Biochemistry, University of Giessen, Germany. Electronic address: Tilman.Borggrefe@biochemie.med.uni-giessen.de.
authors.forename: Tilman
authors.initials: T
authors.lastname: Borggrefe
authors.affiliation: Institute of Molecular Biology and Tumor Research, Philipps University Marburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lauth
authors.affiliation: VIB Center for the Biology of Disease and Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Zwijsen
authors.affiliation: Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Danny
authors.initials: D
authors.lastname: Huylebroeck
authors.affiliation: University Medical Center Ulm, Department of Internal Medicine I, Ulm, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Oswald
authors.affiliation: Institute of Biochemistry, University of Giessen, Germany.
authors.forename: Benedetto Daniele
authors.initials: BD
authors.lastname: Giaimo
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D008954:Models, Biological; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D053823:Hedgehog Proteins; D051880:Receptors, Notch; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins
keywords: Hydroxylation; Methylation; Notch signal transduction; Post-translational modifications; Signaling crosstalk; Transcription factor Hes1.