The amyloid precursor protein and its network of interacting proteins: physiological and pathological implications.
The amyloid precursor protein (APP) is an ubiquitous receptor-like molecule involved in the pathogenesis of Alzheimer's disease that generates beta-amyloid peptides and causes plaque formation. APP and some of its C-terminal proteolytic fragments (CTFs) have also been shown to be in the center of a complex protein-protein network, where selective phosphorylation of APP C-terminus may regulate the interaction with cytosolic phosphotyrosine binding (PTB) domain or Src homology 2 (SH2) domain containing proteins involved in cell signaling. We have recently described an interaction between tyrosine-phosphorylated CTFs and ShcA adaptor protein which is highly enhanced in AD brain, and a new interaction between APP and the adaptor protein Grb2 both in human brain and in neuroblastoma cultured cells. These data suggest a possible role in cell signaling for APP and its CTFs, in a manner similar to that previously reported for other receptors, through a tightly regulated coupling with intracellular adaptors to control the signaling of the cell. In this review, we discuss the significance of these novel findings for AD development.
Russo
Claudio
C
Section of Pharmacology and Neuroscience, Department of Oncology, Biology and Genetics, University of Genova, Italy. russo@cba.unige.it
Venezia
Valentina
V
Repetto
Emanuela
E
Nizzari
Mario
M
Violani
Elisabetta
E
Carlo
Pia
P
Schettini
Gennaro
G
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000544:Alzheimer Disease; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000378:metabolism / Q000473:pathology; D010450:Endopeptidases / Q000145:classification / Q000378:metabolism; D051380:GRB2 Adaptor Protein; D006801:Humans; D008959:Models, Neurological; D010766:Phosphorylation; D011485:Protein Binding; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D014443:Tyrosine; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human