Notch signaling is a highly conserved cell communication system that regulates a wide variety of cell types throughout development and into adulthood. Defects in Notch signal transduction have been implicated in a number of human disease states including cancer, stroke, and Alzheimer's disease, underscoring the importance of understanding the basic mechanisms of Notch signal transduction. Cell-surface Notch receptors, following engagement with cell-surface ligands, undergo a series of proteolytic cleavage events which release the intracellular domain of Notch. This proteolytic fragment translocates to the nucleus of the signal receiving cell where it directly regulates transcription of Notch target genes. Based on studies in Drosophila, a model for Notch signaling has been proposed in which the ligand-signaling cell plays an active role in Notch activation beyond ligand presentation. These models propose that during signal transduction the ligand cell actively removes the Notch extracellular domain through the poorly understood phenomenon of trans-endocytosis. This proposal aims to determine if trans-endocytosis is a characteristic of ligand- induced Notch signaling in mammals. To this end, a coculture system that can be examined by confocal microscopy has been developed. This coculture paradigm will allow characterization of the specifics of Notch transfer to Delta cells, providing insight into the molecular mechanism of trans-endocytosis and its relevance to Notch signaling. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31EB006278-02
Application #
7386757
Study Section
Special Emphasis Panel (ZRG1-F05-J (20))
Program Officer
Erim, Zeynep
Project Start
2007-03-01
Project End
2008-06-30
Budget Start
2008-02-29
Budget End
2008-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$12,846
Indirect Cost
Name
University of California Los Angeles
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Nichols, James T; Miyamoto, Alison; Weinmaster, Gerry (2007) Notch signaling--constantly on the move. Traffic 8:959-69
Nichols, James T; Miyamoto, Alison; Olsen, Samantha L et al. (2007) DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur. J Cell Biol 176:445-58