Receptor clustering is involved in Reelin signaling.
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.
Strasser
Vera
V
Max F. Perutz Laboratories, University Departments at the Vienna Biocenter, Department of Medical Biochemistry, University of Vienna, Vienna, Austria.
Fasching
Daniela
D
Hauser
Christoph
C
Mayer
Harald
H
Bock
Hans H
HH
Hiesberger
Thomas
T
Herz
Joachim
J
Weeber
Edwin J
EJ
Sweatt
J David
JD
Pramatarova
Albéna
A
Howell
Brian
B
Schneider
Wolfgang J
WJ
Nimpf
Johannes
J
D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D019281:Dimerization; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism*; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D015398:Signal Transduction / Q000502:physiology*
D015816:Cell Adhesion Molecules, Neuronal; C103773:Dab1 protein, mouse; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D000091042:Reelin Protein; C000717129:Reln protein, rat; C469363:reelin receptor; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases