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J. Biol. Chem., Vol. 282, Issue 18, 13833-13844, May 4, 2007

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Amyloid Precursor Protein and Presenilin1 Interact with the Adaptor GRB2 and Modulate ERK 1,2 Signaling^*

Mario Nizzari¹, Valentina Venezia¹, Emanuela Repetto¹², Valentina Caorsi^¶, Raffaella Magrassi^¶, Maria Cristina Gagliani^¶||**, Pia Carlo, Tullio Florio, Gennaro Schettini, Carlo Tacchetti^¶||**, Tommaso Russo, Alberto Diaspro^¶**, and Claudio Russo³

From the Dipartimento di Oncologia, Biologia e Genetica, Università di Genova, Viale Benedetto XV, 2, 16132 Genova, LAMBS, Dipartimento di Fisica, Università di Genova, Genova, ^¶MicroscoBio Research Center, Università di Genova, Via Dodecaneso 33, 16146 Genova, ^||Dipartimento di Medicina Sperimentale, Università di Genova, Via de Toni 14, 16132 Genova, ^**FIRC Institute of Molecular Oncology, Via de Toni 14, 16132 Genova, CEINGE Biotecnologie Avanzate, Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, Via Comunale Margherita 482, 80131 Napoli, and Dipartimento di Scienze per la Salute, Università del Molise, Via De Sanctis, 86100 Campobasso, Italy

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- 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- 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.

Received for publication, October 30, 2006 , and in revised form, February 20, 2007.

^* This work was supported by European Community Contract LSHM-CT-2003-503330/APOPIS, Alzheimer Association Grant IIRG-02-3976, Ministero dell'Università e Ricerca Grant FIRB RBNE01ARR4-08, The CARIGE Foundation, The Enrico and Roberta Tadiotto Fund (to C. R.), the San Paolo Foundation (to C. T.), and by Ministero dell'Università e Ricerca Grant FIRB RBNE01FEJ7-006 (to P. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

¹ These authors contributed equally to this work.

² Present address: Dept. of Neurosciences, University of California, San Diego, CA 92093-0662.

³ To whom correspondence should be addressed. E-mail: Claudio.Russo{at}unimol.it.

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