Amyloid precursor protein and presenilin1 interact with the adaptor GRB2 and modulate ERK1,2 signaling

Mario Nizzari, Valentina Venezia, Emanuela Repetto, Valentina Caorsi, Raffaella Magrassi, Maria Cristina Gagliani, Pia Carlo, Tullio Florio, Gennaro Schettini, Carlo Tacchetti, Tommaso Russo, Alberto Diaspro, Claudio Russo

Research output: Contribution to journalArticle

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-β 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-β 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.

Original languageEnglish
Pages (from-to)13833-13844
Number of pages12
JournalJournal of Biological Chemistry
Volume282
Issue number18
DOIs
Publication statusPublished - May 4 2007

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry

Cite this

Nizzari, M., Venezia, V., Repetto, E., Caorsi, V., Magrassi, R., Gagliani, M. C., Carlo, P., Florio, T., Schettini, G., Tacchetti, C., Russo, T., Diaspro, A., & Russo, C. (2007). Amyloid precursor protein and presenilin1 interact with the adaptor GRB2 and modulate ERK1,2 signaling. Journal of Biological Chemistry, 282(18), 13833-13844. https://doi.org/10.1074/jbc.M610146200