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Cited by 116Blood Coagulation and Thrombosis MechanismsProtein Kinase Regulation and GTPase SignalingProtease and Inhibitor Mechanisms

Activated protein C ligation of ApoER2 (LRP8) causes Dab1-dependent signaling in U937 cells

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Yang, Xia V., Banerjee, Yajnavalka, Fernández, José A., Deguchi, Hiroshi, Xu, Xiao, Mosnier, Laurent O., Urbanus, Rolf. T., de Groot, Phillip G. +3 more·2009·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0807594106PMC PMC2629184
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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 3β (GSK3β), 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 GSK3β, 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 , ≈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 GSK3β, thereby contributing to APC's beneficial effects on cells.

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  • In macrophages, ligation of ApoER2 by activated protein C results in Dab1-dependent signaling events.

    “In macrophages, ligation of ApoER2 by activated protein C results in Dab1-dependent signaling events (40).”

    From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [40]

    The Results report that activated protein C induced Dab1 phosphorylation in U937 cells and that ApoER2 knockdown abolished it. The Discussion describes this as ApoER2-mediated, Dab1-dependent signaling, but the study used a monocytic cell line rather than macrophages, so the claim extends the finding to a different cell population. (LLM, conf=0.88)

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  • Phosphorylation of Dab1 downstream of VLDLR and ApoER2 is not limited to the CNS.

    “Furthermore, the phosphorylation of Dab1 downstream of the VLDLR and ApoER2 is not limited to the CNS.”

    From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [40]

    The Results and Discussion show APC-induced Dab1 phosphorylation downstream of ApoER2 in U937 monocytic cells, establishing that this signaling occurs outside the CNS. They do not establish Dab1 phosphorylation downstream of VLDLR outside the CNS; the Discussion instead reports that APC did not bind soluble VLDLR. (LLM, conf=0.87)

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Authors
Yang, X. V., Banerjee, Y., Fernández, J. A., Deguchi, H., Xu, X., Mosnier, L. O., Urbanus, R. T., de Groot, P. G., White-Adams, T. C., McCarty, O. J. T., & Griffin, J. H.
Affiliations
  • Scripps Research Institute (US)
  • University Medical Center Utrecht (NL)
  • Laboratory of Clinical Chemistry and Haematology, University Medical Centre Utrecht, Utrecht, The Netherlands; and
  • Departments of Biomedical Engineering and Cell and Developmental Biology, Oregon Health & Science University, Portland, OR 97239
  • Oregon Health & Science University (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2009-01-06
Volume
106
Issue
1
Pages
274-279
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0807594106
PMC
PMC2629184
OpenAlex
W2039907127
Cited by
116
References
2
Citations by year
2026: 1 · 2025: 4 · 2024: 1 · 2023: 5 · 2022: 5 · 2021: 1 · 2020: 3 · 2019: 2 · 2018: 10 · 2017: 11 · 2016: 7 · 2015: 4 · 2014: 5 · 2013: 12 · 2012: 9
FWCI
7.82
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Heart, Lung, and Blood Institute (HL 31950, R00HL087618, R01HL052246, HL087618, HL-52246, K99HL087618, P01HL031950, R37HL052246)
Topics
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords
activated protein C, ApoER2, LRP8, Disabled-1, receptor-associated protein, Akt, GSK3β, PI3K signaling, U937 cells, monocytic cells, receptor ligation, tissue factor, endotoxin, endothelial protection, protein C receptor, protease-activated receptor 1
MeSH terms
Blood Coagulation Factors, Humans, Monocytes, Nerve Tissue Proteins, Phosphorylation, Protein Binding, Protein C, Receptors, Cell Surface, Signal Transduction, Receptors, Lipoprotein, Phosphatidylinositol 3-Kinases, U937 Cells, LDL-Receptor Related Proteins, Glycogen Synthase Kinase 3, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-akt

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