title: The cell giveth and the cell taketh away: an overview of Notch pathway activation by endocytic trafficking of ligands and receptors.
abstract: Notch signaling is firmly established as a form of cell-to-cell communication that is critical throughout development. Dysregulation of Notch has been linked to cancer and developmental disorders, making it an important target for therapeutic intervention. One aspect of this pathway that sets it apart from others is its apparent reliance on endocytosis by signal-sending and signal-receiving cells. The subtle details of endocytosis-mediated molecular processing within both ligand- and receptor-presenting cells that are required for the Notch signal to maintain fidelity remain unclear. The endosomal system has long been known to play an important role in terminating signal transduction by directing lysosomal trafficking and degradation of cell surface receptors. More recently, endocytic trafficking has also been shown to be critical for activation of signaling. This review highlights four models of endocytic processing in the context of the Notch pathway. In ligand-presenting cells, endocytosis may be required for pre-processing of ligands to make them competent for interaction with Notch receptors and/or for exerting a pulling force on the ligand/Notch complex. In receptor-presenting cells, endocytosis may be a prerequisite for Notch cleavage and thus activation and/or it could be a means of limiting ligand-independent Notch activation. Recent advances in our understanding of how and why endocytosis of Notch receptors and ligands is required for activation and termination of signaling during normal development and in disease states are discussed.
authors.affiliation: Center for Research on Occupational and Environmental Toxicology, School of Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA.
authors.forename: Emily B
authors.initials: EB
authors.lastname: Pratt
authors.forename: Jill S
authors.initials: JS
authors.lastname: Wentzell
authors.forename: Julia E
authors.initials: JE
authors.lastname: Maxson
authors.forename: Lauren
authors.initials: L
authors.lastname: Courter
authors.forename: Dennis
authors.initials: D
authors.lastname: Hazelett
authors.forename: Jan L
authors.initials: JL
authors.lastname: Christian
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000737:chemistry / Q000502:physiology*; D004705:Endocytosis; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D021381:Protein Transport; D051880:Receptors, Notch / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008024:Ligands; D051880:Receptors, Notch