ArticleProceedings of the National Academy of Sciences of the United States of America2009
Activated protein C ligation of ApoER2 (LRP8) causes Dab1-dependent signaling in U937 cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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71 citing papers in PubMed, 117 citations in OpenAlex.
- Macrophage Dab1 Links Early Hypoxia to Adaptive Angiogenesis to Drive Peripheral Nerve Repair.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
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- Endothelial protein C receptor promotes retinal neovascularization through heme catabolism.Nature communications · 2025Article
- Effect of PCSK9 Inhibitors on Regulators of Lipoprotein Homeostasis, Inflammation and Coagulation.Biomedicines · 2025Article
- A Microflow Chip Technique for Monitoring Platelets in Late Pregnancy: A Possible Risk Factor for Thrombosis.Journal of blood medicine · 2025Article
- An orthosteric/allosteric bivalent peptide agonist comprising covalently linked protease-activated receptor-derived peptides mimics in vitro and in vivo activities of activated protein C.Journal of thrombosis and haemostasis : JTH · 2024Article
- Role of Lipid Rafts on LRP8 Signaling Triggered by Anti-β2-GPI Antibodies in Endothelial Cells.Biomedicines · 2023Article
- Bacterial-Type Long-Chain Polyphosphates Bind Human Proteins in the Phosphatidylinositol Signaling Pathway.Thrombosis and haemostasis · 2022Article
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- Protein C Pathway in Paediatric and Neonatal Sepsis.Frontiers in pediatrics · 2021Review
- Podocyte Integrin-Journal of the American Society of Nephrology : JASN · 2020Article
- Lipoprotein receptor signalling in atherosclerosis.Cardiovascular research · 2020Review
- The Cardioprotective Signaling Activity of Activated Protein C in Heart Failure and Ischemic Heart Diseases.International journal of molecular sciences · 2019Review
- Targeting LRP8 inhibits breast cancer stem cells in triple-negative breast cancer.Cancer letters · 2018Article
- Review
- New Insights in the Pathophysiology of Antiphospholipid Syndrome.Seminars in thrombosis and hemostasis · 2018Review
- Article
- Article
- Regulation of immune cell signaling by activated protein C.Journal of leukocyte biology · 2018Review
- PAR1 biased signaling is required for activated protein C in vivo benefits in sepsis and stroke.Blood · 2018Article
11 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
Binding of activated protein C (APC) to cells triggers multiple beneficial cytoprotective activities that suppress apoptosis, inflammation, and endothelial barrier breakdown. One paradigm for APC's signaling emphasizes its binding to endothelial cell protein C receptor (EPCR) and subsequent protease activated receptor (PAR)-1 activation. Here we used human monocytic-like U937 cells to evaluate apolipoprotein E receptor 2 (ApoER2)-dependent signaling by APC and found that APC initiated rapid phosphorylation of Tyr-220 in the adaptor protein disabled-1 (Dab1) and of Ser-473 in Akt. APC also induced phosphorylation of Ser-9 in glycogen synthase kinase 3beta (GSK3beta), which was blocked by the PI3K inhibitor LY294002. Receptor-associated protein (RAP), a general antagonist for binding of ligands to LDL receptor family members, inhibited APC-induced phosphorylation of Dab1 and GSK3beta, whereas anti-EPCR or anti-PAR1 blocking antibodies did not. Knocking down ApoER2 by using siRNA-ablated APC induced Dab1 phosphorylation, suggesting that RAP-sensitive APC-induced signaling requires ApoER2. In surface plasmon resonance equilibrium binding studies, APC bound with high affinity to soluble (s) ApoER2 (apparent K(d), approximately 30 nM) but not to soluble very low density lipoprotein receptor. RAP blocked APC binding to sApoER2 but not to sEPCR. RAP blocked binding of U937 cells to immobilized APC. RAP also blocked APC's ability to inhibit endotoxin-induced tissue factor pro-coagulant activity of U937 cells. Thus, we propose that ligation of ApoER2 by APC signals via Dab1 phosphorylation and subsequent activation of PI3K and Akt and inactivation of GSK3beta, thereby contributing to APC's beneficial effects on cells.
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