Roles for Glycosylation in Notch Signaling

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Notch receptors are cell surface
glycoproteins that transduce signals to control cell fate and cell division in
metazoans. Constitutive or disregulated signaling leads to developmental
defects and cancer. The ligands that bind to Notch and stimulate signal
transduction are Delta and Serrate/Jagged. We have shown in collaboration with
others that Drosophila and mammalian fringe proteins have a
beta3N-acetylglucosaminyltransferase activity and act directly on Notch to add
GIcNAc to O-fucose on Notch EGF repeats, thereby modulating ligand-induced
Notch signaling. In Drosophila and mammalian cells, fringe acts cell
autonomously to inhibit the Notch response to Serrate(Jagged) while
potentiating the Notch response to Delta. We have used a co-culture reporter
assay to show that manic or lunatic fringe in Notch expressing CHO cells
inhibit the response to Jagged1. We have used a panel of CHO glycosylation
mutants to show that inhibition of Notch signaling by fringe does not require
complex or hybrid N-glycans or sialic acid but does require the action of
fringe on O-fucose attached to Notch EGF repeats, and the subsequent action of
beta4GalT- 1. Thus O. fucosyltransferase and beta4GalT-1 are novel modulators
of Notch signaling. Using CHO glycosylation mutants, co-culture Notch signaling
and soluble ligand binding assays, and mouse mutants, we propose 1 )To identify
the different 0-fucose glycans required for Jagged- and Delta-induced signaling
by Notch receptors 1, 2, 3 and 4 and for the modulation of Notch signaling by
mammalian fringes (manic, lunatic and radical); 2) To determine the biochemical
mechanism by which fringe action perturbs Notch signaling; and 3) To identify
in vivo consequences to Notch signaling in the mouse of inactivating the genes
encoding new modulators of Notch signaling.
StatusFinished
Effective start/end date4/1/023/31/03

Funding

  • National Cancer Institute: $371,346.00

ASJC

  • Developmental Neuroscience
  • Biochemistry
  • Cancer Research
  • Cell Biology
  • Developmental Biology

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