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Identification of integrin αMβ2 as an adhesion receptor on peripheral blood monocytes for Cyr61 (CCN1) and connective tissue growth factor (CCN2): immediate-early gene products expressed in atherosclerotic lesions
Abstract
Cysteine-rich 61 (Cyr61, CCN1) and connective tissue growth factor (CTGF, CCN2) are growth factor–inducible immediate-early gene products found in blood vessel walls and healing cutaneous wounds. We previously reported that the adhesion of endothelial cells, platelets, and fibroblasts to these extracellular matrix–associated proteins is mediated through integrin receptors. In this study, we demonstrated that both Cyr61 and CTGF are expressed in advanced atherosclerotic lesions of apolipoprotein E–deficient mice. Because monocyte adhesion and transmigration are important for atherosclerosis, wound healing, and inflammation, we examined the interaction of THP-1 monocytic cells and isolated peripheral blood monocytes with Cyr61 and CTGF. THP-1 cells and monocytes adhered to Cyr61- or CTGF-coated wells in an activation-dependent manner and this process was mediated primarily through integrin αMβ2. Additionally, expression of αMβ2 on human embryonic kidney 293 cells resulted in enhanced cell adhesion to Cyr61. Consistent with these data, a GST-fusion protein containing the I domain of the integrin αM subunit bound specifically to immobilized Cyr61 or CTGF. We have also investigated the requirement of cell surface heparan sulfate proteoglycans (HSPGs) as coreceptors for monocyte adhesion to Cyr61. Pretreatment of monocytes with heparin or heparinase I resulted in partial inhibition of cell adhesion to Cyr61. However, monocytes, but not fibroblasts, were capable of adhering to a Cyr61 mutant deficient in heparin binding activity. Collectively, these results show that activated monocytes adhere to Cyr61 and CTGF through integrin αMβ2 and cell surface HSPGs. However, unlike fibroblast adhesion to Cyr61, cell surface HSPGs are not absolutely required for this adhesion process.
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In the citing paper
“Subsequent studies have shown that CCN1 supports cell adhesion by binding integrins α6β1 and HSPGs in fibroblasts and smooth muscle cells [55,56], αIIbβ3 in activated platelets [57], αMβ2 in monocytes and macrophages [58,59], and αDβ2 in macrophage foam cells [60].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [58]
In the citing paper
“Furthermore, CCN1 supports the adhesion of activated monocytes through integrin αMβ2, and reprograms macrophages towards M1 polarization through αMβ2-mediated activation of NF-κB [58,59].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [58]
In the citing paper
“CCN1 is overexpressed in vascular smooth muscle cells of atherosclerotic lesions and in the neointima of restenosis after balloon angioplasty, both in rodent models and in humans [23,56,58,135].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [58]
In the citing paper
“Furthermore, CCN1 supports the adhesion of activated monocytes through integrin αMβ2, and reprograms macrophages towards M1 polarization through αMβ2-mediated activation of NF-κB [58,59].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [58]
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Metadata
- Authors
- Schober, J. M., Chen, N., Grzeszkiewicz, T. M., Jovanovic, I., Emeson, E. E., Ugarova, T. P., Ye, R. D., Lau, L. F., & Lam, S. C.-T.
- Affiliations
- Cleveland Clinic (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2002-06-15
- Volume
- 99
- Issue
- 12
- Pages
- 4457-4465
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2048563910
- Cited by
- 242
- References
- 54
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 6 · 2023: 7 · 2022: 6 · 2021: 15 · 2020: 8 · 2019: 12 · 2018: 8 · 2017: 11 · 2016: 14 · 2015: 9 · 2014: 8 · 2013: 11 · 2012: 10
- FWCI
- 8.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ca080080-05)
- National Heart, Lung, and Blood Institute (HL07829, HL41793, HL 63199, R01HL063199)
- National Cancer Institute (CA-80080, R01CA046565, CA-46565)
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- Mac-1, CYR61, connective tissue growth factor, monocyte adhesion, monocyte transmigration, atherosclerosis, heparan sulfate proteoglycans, ApoE-deficient mice, THP-1 cells, integrin I domain, cell adhesion, wound healing
- MeSH terms
- Animals, Apolipoproteins E, Arteriosclerosis, Cell Adhesion, Disease Models, Animal, Growth Substances, Humans, Immunohistochemistry, Monocytes, Protein Binding, Integrins, Macrophage-1 Antigen, Protein Structure, Tertiary, Immediate-Early Proteins, Mice, Knockout, Intercellular Signaling Peptides and Proteins, Mice, Connective Tissue Growth Factor, Cysteine-Rich Protein 61
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