Amyloid precursor protein and Presenilin1 interact with the adaptor GRB2 and modulate ERK 1,2 signaling.
The amyloid precursor protein (APP) and the presenilins 1 and 2 are genetically linked to the development of familial Alzheimer disease. APP is a single-pass transmembrane protein and precursor of fibrillar and toxic amyloid-beta peptides, which are considered responsible for Alzheimer disease neurodegeneration. Presenilins are multipass membrane proteins, involved in the enzymatic cleavage of APP and other signaling receptors and transducers. The role of APP and presenilins in Alzheimer disease development seems to be related to the formation of amyloid-beta peptides; however, their physiological function, reciprocal interaction, and molecular mechanisms leading to neurodegeneration are unclear. APP and presenilins are also involved in multiple interactions with intracellular proteins, the significance of which is under investigation. Among the different APP-interacting proteins, we focused our interest on the GRB2 adaptor protein, which connects cell surface receptors to intracellular signaling pathways. In this study we provide evidence by co-immunoprecipitation experiments, confocal and electron microscopy, and by fluorescence resonance energy transfer experiments that both APP and presenilin1 interact with GRB2 in vesicular structures at the centrosome of the cell. The final target for these interactions is ERK1,2, which is activated in mitotic centrosomes in a PS1- and APP-dependent manner. These data suggest that both APP and presenilin1 can be part of a common signaling pathway that regulates ERK1,2 and the cell cycle.
Nizzari
Mario
M
Dipartimento di Oncologia, Biologia e Genetica, Università di Genova, Viale Benedetto XV, 2, 16132 Genova, Italy.
Venezia
Valentina
V
Repetto
Emanuela
E
Caorsi
Valentina
V
Magrassi
Raffaella
R
Gagliani
Maria Cristina
MC
Carlo
Pia
P
Florio
Tullio
T
Schettini
Gennaro
G
Tacchetti
Carlo
C
Russo
Tommaso
T
Diaspro
Alberto
A
Russo
Claudio
C
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D002460:Cell Line; D002503:Centromere / Q000378:metabolism / Q000648:ultrastructure; D031541:Fluorescence Resonance Energy Transfer; D051380:GRB2 Adaptor Protein / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D053764:Presenilin-1 / Q000378:metabolism*; D053766:Presenilin-2 / Q000378:metabolism; D011485:Protein Binding
D016564:Amyloid beta-Protein Precursor; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3