Functional Importance of Covalent Homodimer of Reelin Protein Linked via Its Central Region

Yasui, Norio; Kitago, Yu; Beppu, Ayako; Kohno, Takao; Morishita, Shunshuke; Gomi, Hiroaki; Nagae, Masamichi; Hattori, Mitsuharu; Takagi, Junichi

doi:10.1074/jbc.m111.242719

Cited by 37 publications

(41 citation statements)

References 41 publications

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“…Reelin dimer formation is required for the full biological activity of the protein and to transduce its signaling [23,24]. Secreted disulfide-linked homodimer of Reelin are the forms found in vivo in brain and plasma [14,25,26].…”

Section: Resultsmentioning

confidence: 99%

Beta-Amyloid Impairs Reelin Signaling

et al. 2013

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Reelin is a signaling protein increasingly associated with the pathogenesis of Alzheimer’s disease that relevantly modulates tau phosphorylation. We have previously demonstrated that β-amyloid peptide (Aβ) alters reelin expression. We have now attempted to determine whether abnormal reelin triggered by Aβ will result in signaling malfunction, contributing to the pathogenic process. Here, we show that reelin forms induced by β-amyloid are less capable of down-regulating tau phosphorylation via disabled-1 and GSK3β kinase. We also demonstrate that the scaffold protein 14-3-3 that increases tau phosphorylation by modulating GSK3β activity, is up-regulated during defective reelin signaling. Binding of reelin to its receptor, mainly ApoER2 in the brain, relays the signal into the cell. We associate the impaired reelin signaling with inefficiency of reelin in forming active homodimers and decreased ability to bind efficiently to its receptor, ApoER2. More remarkably, reelin from Alzheimer cortex shows a tendency to form large complexes instead of homodimers, the active form for signaling. Our results suggest that reelin expression is altered by Aβ leading to impaired reelin signaling.

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Section: Resultsmentioning

confidence: 99%

Beta-Amyloid Impairs Reelin Signaling

et al. 2013

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“…Reelin achieves this task by forming homodimers, which are able to bind at least two receptors (38). Secreted clusterin itself is a heterodimer formed by a ␣-and a ␤-chain generated by proteolytic cleavage of a common precursor.…”

Section: Resultsmentioning

confidence: 99%

“…Reelin achieves this task by forming homodimers, which are able to bind at least two receptors (38). Thrombospondin-1, another functional ligand for ApoER2 and VLDLR, forms homotrimers and is also able to signal along the same pathway (15).…”

Section: Discussionmentioning

confidence: 99%

Clusterin Is a Ligand for Apolipoprotein E Receptor 2 (ApoER2) and Very Low Density Lipoprotein Receptor (VLDLR) and Signals via the Reelin-signaling Pathway

Leeb

Eresheim

Nimpf

2014

Journal of Biological Chemistry

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Background: Clusterin is a highly conserved glycoprotein with broad tissue distribution but enigmatic biological functions. Results: Clusterin signals via the lipoprotein receptors ApoER2 and VLDLR and stimulates cell proliferation in subventricular zone explants enabling neuronal outgrowth. Conclusion: Clusterin-mediated signaling is essential for neuronal chain formation in vitro. Significance: Discovery of a novel function of clusterin in neurogenesis.

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“…F-spondin is a secreted protein involved in axonal growth (13). Both ligands have domains to induce dimerization (27,37), and both bind ApoER2 and VLDLR and activate Dab-1 phosphorylation (6,11,12,19,39,41). As above, we transfected COS-7 cells with HA-tagged and untagged ApoER2 and treated the cells for 1 h with ligand.…”

Section: Dimeric Ligands Induce Apoer2mentioning

confidence: 99%

“…Many of these receptors have N-terminal domains that bind multivalent ligands and catalyze subsequent signaling through receptor autophosphorylation and phosphorylation of tyrosine kinase substrates. Reelin and F-spondin are both oligomeric/dimeric ligands (21,27,37), and both promote intracellular signaling cascades (12, 38 -42). Here we show strong clustering of ApoER2 induced by F-spondin and Reelin but relatively weak clustering with the ligand apoE.…”

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confidence: 99%