Processing of the recycling
proteoglycan glypican-1 involves the release of its
heparan sulfate chains by
copper ion- and
nitric oxide-catalyzed ascorbate-triggered autodegradation. The
Alzheimer disease amyloid precursor
protein (APP) and its paralogue, the
amyloid precursor-like
protein 2 (APLP2), contain
copper ion-,
zinc ion-, and
heparan sulfate-binding domains. We have investigated the possibility that APP and APLP2 regulate
glypican-1 processing during endocytosis and recycling. By using cell-free biochemical experiments, confocal
laser immunofluorescence microscopy, and flow cytometry of tissues and cells from wild-type and knock-out mice, we find that (a) APP and
glypican-1 colocalize in perinuclear compartments of
neuroblastoma cells, (b) ascorbate-triggered nitric oxidecatalyzed
glypican-1 autodegradation is
zinc ion-dependent in the same cells, (c) in cell-free experiments, APP but not APLP2 stimulates
glypican-1 autodegradation in the presence of both Cu(II) and Zn(II)
ions, whereas the Cu(I) form of APP and the Cu(II) and Cu(I) forms of APLP2 inhibit autodegradation, (d) in primary cortical neurons from APP or APLP2 knock-out mice, there is an increased
nitric oxide-catalyzed degradation of
heparan sulfate compared with brain tissue and neurons from wild-type mice, and (e) in growth-quiescent fibroblasts from APLP2 knock-out mice, but not from APP knock-out mice, there is also an increased
heparan sulfate degradation. We propose that the rate of autoprocessing of
glypican-1 is modulated by APP and APLP2 in neurons and by APLP2 in fibroblasts. These observation identify a functional relationship between the
heparan sulfate and
copper ion binding activities of APP/APLP2 in their modulation of the
nitroxyl anion-catalyzed
heparan sulfate degradation in
glypican-1.