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Apoptotic Cell Death and Amyloid Precursor Protein Signaling in Neuroblastoma SH‐SY5Y Cells
Author(s) -
VENEZIA VALENTINA,
RUSSO CLAUDIO,
REPETTO EMANUELA,
NIZZARI MARIO,
VIOLANI ELISABETTA,
CARLO PIA,
MARCHETTI BIANCA,
SCHETTINI GENNARO
Publication year - 2004
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1329.042
Subject(s) - grb2 , tyrosine phosphorylation , sh sy5y , microbiology and biotechnology , amyloid precursor protein , phosphorylation , biology , apoptosis , signal transducing adaptor protein , signal transduction , cancer research , chemistry , biochemistry , cell culture , neuroblastoma , alzheimer's disease , medicine , genetics , disease
A bstract : We have recently shown that the amyloid precursor protein (APP) and a subset of its C‐terminal fragments (CTFs) are tyrosine phosphorylated in human brain and in cultured cells. Tyrosine phosphorylation generates a substrate that is sequentially bound by the adaptor proteins ShcA and Grb2, and this interaction is significantly enhanced in Alzheimer's disease brains. Here we have studied the APP/CTFs phosphorylation and ShcA activation in a human neuroblastoma cell line, SH‐SY5Y, under basal and apoptotic conditions. To commit these cells to apoptosis, we used staurosporin, a well‐known apoptotic inducer and protein kinase C blocker. Our data suggest the following: (1) in normally proliferating SH‐SY5Y cells, full‐length APP is complexed with Grb2[Q3], likely through its SH2 domain; (2) upon induction of apoptosis, APP is degraded and ShcA‐Grb2 coimmunoprecipitates with CTFs recognized by anti‐APP antibodies; and (3) caspase inhibitors partially block the degradation of APP and the coprecipitation of CTFs with ShcA‐Grb2 adaptors. In summary, our data suggest that in SH‐SY5Y cells, tyrosine‐phosphorylated APP is involved in a complex with ShcA‐Grb2 adaptors that is disrupted during apoptosis. The abnormal degradation of APP and consequent increased levels of CTFs (as has been observed in Alzheimer's disease and Down's syndrome) generate a complex between tyrosine‐phosphorylated CTFs and intracellular adaptors. The signaling through APP and its CTFs may have significant relevance for apoptotic cell death in Alzheimer's disease.