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J. Biol. Chem., Vol. 279, Issue 32, 33471-33479, August 6, 2004

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Apolipoprotein E Receptors Are Required for Reelin-induced Proteasomal Degradation of the Neuronal Adaptor Protein Disabled-1^*

Hans H. Bock¶||, Yves Jossin**, Petra May¶, Oliver Bergner¶, and Joachim Herz¶¶¶

From the Department of Medicine II and Zentrum für Neurowissenschaften, Albert-Ludwigs-Universität, Albertstrasse 23, 79104 Freiburg, Germany, the ^¶Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, and the ^**Developmental Genetics Unit, Université Catholique de Louvain, UCL 7382, 73 Avenue E. Mounier, B1200 Brussels, Belgium

The cytoplasmic adaptor protein Disabled-1 (Dab1) is necessary for the regulation of neuronal positioning in the developing brain by the secreted molecule Reelin. Binding of Reelin to the neuronal apolipoprotein E receptors apoER2 and very low density lipoprotein receptor induces tyrosine phosphorylation of Dab1 and the subsequent activation or relocalization of downstream targets like phosphatidylinositol 3 (PI3)-kinase and Nck. Disruption of Reelin signaling leads to the accumulation of Dab1 protein in the brains of genetically modified mice, suggesting that Reelin limits its own action in responsive neurons by down-regulating the levels of Dab1 expression. Here, we use cultured primary embryonic neurons as a model to demonstrate that Reelin treatment targets Dab1 for proteolytic degradation by the ubiquitin-proteasome pathway. We show that tyrosine phosphorylation of Dab1 but not PI3-kinase activation is required for its proteasomal targeting. Genetic deficiency in the Dab1 kinase Fyn prevents Dab1 degradation. The Reelin-induced Dab1 degradation also depends on apoER2 and very low density lipoprotein receptor in a gene-dose dependent manner. Moreover, pharmacological blockade of the proteasome prevents the formation of a proper cortical plate in an in vitro slice culture assay. Our results demonstrate that signaling through neuronal apoE receptors can activate the ubiquitin-proteasome machinery, which might have implications for the role of Reelin during neurodevelopment and in the regulation of synaptic transmission.

Received for publication, February 18, 2004 , and in revised form, May 17, 2004.

^* This work was supported in part by National Institutes of Health Grants HL20948, HL63762, and NS43408, the Alzheimer's Association, the Wolfgang-Paul Award of the Humboldt Foundation, the Perot Family Foundation (to J. H.), and an Emmy Noether fellowship of the Deutsche Forschungsgemeinschaft (to P. M.). 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.

Postdoctoral fellow supported by the Fondation Médicale Reine Elisabeth.

Supported by the Boehringer Ingelheim-Fonds. Present address: Dept. of Biochemistry, Johannes-Gutenberg-Universität, Becherweg 30, 55099 Mainz, Germany.

^|| To whom correspondence may be addressed. Tel.: 49-761-203-8421; Fax: 49-761-203-8433; E-mail: hans.bock{at}zfn.uni-freiburg.de.

^¶¶ To whom correspondence may be addressed. E-mail: joachim.herz{at}utsouthwestern.edu.

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