Signal transduction through tyrosine-phosphorylated carboxy-terminal fragments of APP via an enhanced interaction with Shc/Grb2 adaptor proteins in reactive astrocytes of Alzheimer's disease brain.
The processing of the amyloid precursor protein (APP) through the formation of C-terminal fragments (CTFs) and the production of beta-amyloid, are events likely to influence the development and the progression of Alzheimer's disease (AD). APP is a transmembrane protein similar to a cell-surface receptor with the intraluminal NPTY motif in the cytosolic C terminus. Although APP holoprotein can be bound to intracellular proteins like Fe65, X11, and mDab, the ultimate function and the mechanisms through which this putative receptor transfers its message are unclear. Here it is shown that in human brain, a subset of tyrosine-phosphorylated CTFs represent docking sites for the adaptor protein ShcA. ShcA immunoreactivity is greatly enhanced in Alzheimer's patients; it is mainly localized to glial cells and occurs at reactive astrocytes surrounding cerebral vessels and amyloid plaques. Grb2 also is involved in complexes with ShcA and tyrosine-phosphorylated CTFs, and in AD brain the interaction between Grb2-ShcA and CTFs is enhanced. Also, a higher amount of phospho-ERK1,2 is present in AD brain in comparison with control cases, likely as a result of the ShcA activation. In vitro experiments show that the ShcA-CTFs interaction is strictly confined to glial cells when treated with thrombin, which is a well-known ShcA and ERK1,2 activator, mitogen, and regulator of APP cleavage. In untreated cells ShcA does not interact with either APP or CTFs, although they are normally produced. Altogether these data suggest that CTFs are implicated in cell signaling via Shc transduction machinery, likely influencing MAPK activity and glial reaction in AD patients.
Russo
Claudio
C
Sezione di Farmacologia, Dipartimento Oncologia Biologia e Genetica, Università di Genova, Dipartimento di Farmacologia e Neuroscienze IST c/o Centro di Biotecnologie Avanzate, Largo R. Benzi 10, 16132 Genoa, Italy.
Dolcini
Virginia
V
Salis
Serena
S
Venezia
Valentina
V
Violani
Elisabetta
E
Carlo
Pia
P
Zambrano
Nicola
N
Russo
Tommaso
T
Schettini
Gennro
G
D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000494:pharmacology*; D001253:Astrocytes / Q000473:pathology / Q000502:physiology*; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D051380:GRB2 Adaptor Protein; D006801:Humans; D008875:Middle Aged; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012016:Reference Values; D015398:Signal Transduction / Q000502:physiology*; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D010446:Peptide Fragments; D011506:Proteins; D019000:Phosphotyrosine