title: Amyloid precursor protein and Presenilin1 interact with the adaptor GRB2 and modulate ERK 1,2 signaling.
abstract: 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.
authors.affiliation: Dipartimento di Oncologia, Biologia e Genetica, Università di Genova, Viale Benedetto XV, 2, 16132 Genova, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Nizzari
authors.forename: Valentina
authors.initials: V
authors.lastname: Venezia
authors.forename: Emanuela
authors.initials: E
authors.lastname: Repetto
authors.forename: Valentina
authors.initials: V
authors.lastname: Caorsi
authors.forename: Raffaella
authors.initials: R
authors.lastname: Magrassi
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Gagliani
authors.forename: Pia
authors.initials: P
authors.lastname: Carlo
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
authors.forename: Gennaro
authors.initials: G
authors.lastname: Schettini
authors.forename: Carlo
authors.initials: C
authors.lastname: Tacchetti
authors.forename: Tommaso
authors.initials: T
authors.lastname: Russo
authors.forename: Alberto
authors.initials: A
authors.lastname: Diaspro
authors.forename: Claudio
authors.initials: C
authors.lastname: Russo
mesh_terms: 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
chemical_list: 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