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Apoptotic cell death influences the signaling activity of the amyloid precursor protein through ShcA and Grb2 adaptor proteins in neuroblastoma SH‐SY5Y cells
Author(s) -
Venezia Valentina,
Russo Claudio,
Repetto Emanuela,
Salis Serena,
Dolcini Virginia,
Genova Francesca,
Nizzari Mario,
Mueller Ulrike,
Schettini Gennaro
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02618.x
Subject(s) - signal transducing adaptor protein , grb2 , sh sy5y , apoptosis , microbiology and biotechnology , chemistry , cancer research , neuroblastoma , signal transduction , biology , biochemistry , cell culture , genetics
The amyloid precursor protein (APP) is an ubiquitous receptor‐like molecule involved in the pathogenesis of Alzheimer's disease (AD). APP and some of its C‐terminal proteolytic fragments (CTFs) have been shown to be phosphorylated and to interact with cytosolic phosphotyrosine binding (PTB) domain containing proteins involved in cell signaling and vesicular transport. Among others, the interaction between tyrosine‐phosphorylated CTFs and ShcA‐Grb2 adaptors is highly enhanced in AD brain. Here we have identified in SH‐SY5Y neuroblastoma cells an interaction between APP holoprotein and the adaptor Grb2. Upon activation of apoptotic cell death this interaction is rapidly degraded, APP is partially cleaved and the complex APP/Grb2 is replaced by a new complex between CTFs and ShcA that still involves Grb2. The formation of these complexes is regulated by beta‐site APP‐cleaving enzyme 1 and influences the phosphorylation of mitogen‐activated protein kinase p44/42 extracellular signal‐regulated kinase as well as the level of apoptotic death of the cells. These data suggest a dual role in cell signaling for APP and its CTFs in neuroblastoma cells, in a manner similar to that previously reported for other tyrosine kinase receptor, through a tightly regulated coupling with alternative intracellular adaptors to control the signaling of the cell.