Receptor Clustering Is Involved in Reelin Signaling

Vera Strasser, Daniela Fasching, Christoph Hauser, Harald Mayer, Hans H. Bock, Thomas Hiesberger, Joachim Herz, Edwin J. Weeber, J. David Sweatt, Albéna Pramatarova, Brian Howell, Wolfgang J. Schneider, Johannes Nimpf

Research output: Contribution to journalArticle

151 Scopus citations

Abstract

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 I (Dabl), 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, Dabl 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.

Original languageEnglish (US)
Pages (from-to)1378-1386
Number of pages9
JournalMolecular and cellular biology
Volume24
Issue number3
DOIs
StatePublished - Feb 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Strasser, V., Fasching, D., Hauser, C., Mayer, H., Bock, H. H., Hiesberger, T., Herz, J., Weeber, E. J., Sweatt, J. D., Pramatarova, A., Howell, B., Schneider, W. J., & Nimpf, J. (2004). Receptor Clustering Is Involved in Reelin Signaling. Molecular and cellular biology, 24(3), 1378-1386. https://doi.org/10.1128/MCB.24.3.1378-1386.2004