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Molecular and Cellular Biology, February 2004, p. 1378-1386, Vol. 24, No. 3
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.3.1378-1386.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Receptor Clustering Is Involved in Reelin Signaling

Vera Strasser,1 Daniela Fasching,1 Christoph Hauser,1 Harald Mayer,1 Hans H. Bock,2 Thomas Hiesberger,2 Joachim Herz,2 Edwin J. Weeber,3 J. David Sweatt,3 Albéna Pramatarova,4 Brian Howell,4 Wolfgang J. Schneider,1 and Johannes Nimpf1*

Max F. Perutz Laboratories, University Departments at the Vienna Biocenter, Department of Medical Biochemistry, University of Vienna, Vienna, Austria,1 Department of Molecular Genetics, UT Southwestern Medical Center, Dallas,2 Division of Neuroscience, Baylor College of Medicine, Houston, Texas,3 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland4

Received 16 June 2003/ Returned for modification 31 July 2003/ Accepted 6 November 2003

The Reelin signaling cascade plays a crucial role in the correct positioning of neurons during embryonic brain development. Reelin binding to apolipoprotein E receptor 2 (ApoER2) and very-low-density-lipoprotein receptor (VLDLR) leads to phosphorylation of disabled 1 (Dab1), an adaptor protein which associates with the intracellular domains of both receptors. Coreceptors for Reelin have been postulated to be necessary for Dab1 phosphorylation. We show that bivalent agents specifically binding to ApoER2 or VLDLR are sufficient to mimic the Reelin signal. These agents induce Dab1 phosphorylation, activate members of the Src family of nonreceptor tyrosine kinases, modulate protein kinase B/Akt phosphorylation, and increase long-term potentiation in hippocampal slices. Induced dimerization of Dab1 in HEK293 cells leads to its phosphorylation even in the absence of Reelin receptors. The mechanism for and the sites of these phosphorylations are identical to those effected by Reelin in primary neurons. These results suggest that binding of Reelin, which exists as a homodimer in vivo, to ApoER2 and VLDLR induces clustering of ApoER2 and VLDLR. As a consequence, Dab1 becomes dimerized or oligomerized on the cytosolic side of the plasma membrane, constituting the active substrate for the kinase; this process seems to be sufficient to transmit the signal and does not appear to require any coreceptor.

* Corresponding author. Mailing address: Department of Medical Biochemistry, Division of Molecular Genetics, Biocenter and University of Vienna, Dr. Bohrgasse 9/2, A-1030 Vienna, Austria. Phone: 43-1-4277-61808. Fax: 43-1-4277-9618. E-mail: Johannes.Nimpf{at}univie.ac.at.

Molecular and Cellular Biology, February 2004, p. 1378-1386, Vol. 24, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.3.1378-1386.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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