Regulation of ApoE receptor proteolysis by ligand binding
Abstract
Two brain receptors for apolipoprotein E (apoE), the apoE receptor 2 (apoEr2) and the very low density lipoprotein receptor (VLDLr), are important in neuronal migration during development. Using a series of tagged constructs, we found that these two receptors undergo extracellular cleavages to release secreted forms of the receptors and intramembranous cleavages to degrade the C-terminal fragments. Release of the extracellular domains was blocked by an inhibitor of metalloproteinases and increased by PMA. Accumulation of the intracellular domain was increased by the presence of an inhibitor of gamma-secretase. ApoE binding to these receptors caused increased release of the extracellular domain and accumulation of the intracellular domains; similar increases in receptor proteolytic domains were observed from endogenous apoEr2 after treatment of primary neurons or rat hippocampus with an apoE-derived peptide. The human apoE isoforms promoted proteolysis to different degrees, with apoE2 resulting in a greater accumulation of the C-terminal fragments of apoEr2 compared with apoE4. These effects of apoE on receptor proteolysis were mediated by the ligand binding domain of the receptor. Similar promotion of receptor cleavage was seen with two other ligands, reelin and activated alpha2-macroglobulin. We suggest that signaling promoted by these receptors depends in part on these regulated proteolytic events.
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DAPT treatment increases ApoER2 CTFs, indicating that γ-secretase is responsible for ApoER2-CTF processing to produce the corresponding intracellular domain (ICD).
“When ApoER2-expressing cells are treated with DAPT, a γ–secretase inhibitor, the amount of CTFs increase [39], [40], indicating that γ–secretase is responsible for the ApoER2-CTF processing to produce the corresponding intracellular domain (ICD).”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [40]
Overexpressing adaptor proteins associated with higher cell surface receptor levels also increases the ApoER2 CTF level.
“When over expressing adaptor proteins, which are associated with higher levels of receptor at the cell surface, the ApoER2 CTF (the product of sheddases and substrate of the γ-secretase complex) is also detected at a higher level [40], [54].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [40]
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- Authors
- Hoe, H.-S., & Rebeck, G. W.
- Affiliations
- Georgetown University (US)
- Corresponding author
- Rebeck, G. William
- Venue
- Molecular Brain Research
- Publisher
- Elsevier BV
- Published
- 2005-06
- Volume
- 137
- Issue
- 1-2
- Pages
- 31-39
- ISSN
- 0169-328X (ISSN-L)
- OpenAlex
- W2059011964
- Cited by
- 85
- References
- 4
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 4 · 2017: 4 · 2016: 5 · 2015: 2 · 2014: 4 · 2013: 3 · 2012: 3
- FWCI
- 5.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG14473)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- apolipoprotein E, VLDLR, receptor proteolysis, ligand binding, metalloproteinase cleavage, gamma-secretase, C-terminal fragment, APOE isoforms, reelin, alpha2-macroglobulin, neuronal migration, hippocampus, primary neurons
- MeSH terms
- Reelin Protein, Animals, Apolipoproteins E, Binding Sites, Binding, Competitive, Cell Membrane, Chlorocebus aethiops, Enzyme Inhibitors, Hippocampus, Humans, Ligands, Male, Peptide Hydrolases, Endopeptidases, Peptides, Protein Binding, Receptors, LDL, Aspartic Acid Endopeptidases, Rats, Sprague-Dawley, Protein Structure, Tertiary, Receptors, Lipoprotein, COS Cells, LDL-Receptor Related Proteins, Rats, Apolipoprotein E4, Apolipoprotein E2, Amyloid Precursor Protein Secretases
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