Activation-dependent Adhesion of Human Platelets to Cyr61 and Fisp12/Mouse Connective Tissue Growth Factor Is Mediated through Integrin αIIbβ3
Open accessAbstract
Cyr61 and connective tissue growth factor (CTGF), members of a newly identified family of extracellular matrix-associated signaling molecules, are found to mediate cell adhesion, promote cell migration and enhance growth factor-induced cell proliferation in vitro, and induce angiogenesis in vivo. We previously showed that vascular endothelial cell adhesion and migration to Cyr61 and Fisp12 (mouse CTGF) are mediated through integrin alpha(v)beta(3). Both Cyr61 and Fisp12/mCTGF are present in normal blood vessel walls, and it has been demonstrated that CTGF is overexpressed in advanced atherosclerotic lesions. In the present study, we examined whether Cyr61 and Fisp12/mCTGF could serve as substrates for platelet adhesion. Agonist (ADP, thrombin, or U46619)-stimulated but not resting platelets adhered to both Cyr61 and Fisp12/mCTGF, and this process was completely inhibited by prostaglandin I(2), which prevents platelet activation. The specificity of Cyr61- and Fisp12/mCTGF-mediated platelet adhesion was demonstrated by specific inhibition of this process with polyclonal anti-Cyr61 and anti-Fisp12/mCTGF antibodies, respectively. The adhesion of ADP-activated platelets to both proteins was divalent cation-dependent and was blocked by RGDS, HHLGGAKQAGDV, or echistatin, but not by RGES. Furthermore, this process was specifically inhibited by the monoclonal antibody AP-2 (anti-alpha(IIb)beta(3)), but not by LM609 (anti-alpha(v)beta(3)), indicating that the interaction is mediated through integrin alpha(IIb)beta(3). In a solid phase binding assay, activated alpha(IIb)beta(3), purified by RGD affinity chromatography, bound to immobilized Cyr61 and Fisp12/mCTGF in a dose-dependent and RGD-inhibitable manner. In contrast, unactivated alpha(IIb)beta(3) failed to bind to either protein. Collectively, these findings identify Cyr61 and Fisp12/mCTGF as two novel activation-dependent adhesive ligands for the integrin alpha(IIb)beta(3) on human platelets, and implicate a functional role for these proteins in hemostasis and thrombosis.
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CCN1 supports cell adhesion by binding integrins α6β1 and HSPGs in fibroblasts and smooth muscle cells, αIIbβ3 in activated platelets, αMβ2 in monocytes and macrophages, and αDβ2 in macrophage foam cells.
“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 [57]
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References 45 · Cited by 204
- Authors
- Jedsadayanmata, A., Chen, C.-C., Kireeva, M. L., Lau, L. F., & Lam, S. C.-T.
- Affiliations
- University of Illinois Chicago (US)
- Corresponding author
- Lam, Stephen C.-T.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-08
- Volume
- 274
- Issue
- 34
- Pages
- 24321-24327
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1996293220
- Cited by
- 204
- References
- 45
- Citations by year
- 2025: 2 · 2023: 1 · 2022: 5 · 2021: 6 · 2019: 3 · 2018: 3 · 2017: 7 · 2016: 3 · 2015: 6 · 2014: 6 · 2013: 7 · 2012: 4
- FWCI
- 7.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ca080080-05)
- National Heart, Lung, and Blood Institute (HL41793)
- National Cancer Institute (CA-80080, R01CA046565, CA-46565)
- Topics
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Keywords
- CYR61, connective tissue growth factor, platelet adhesion, integrin αIIbβ3, platelet activation, extracellular matrix ligands, hemostasis, thrombosis, prostacyclin, RGD peptide, angiogenesis, atherosclerosis, ADP, thrombin, U46619, echistatin
- MeSH terms
- Animals, Arteriosclerosis, Growth Substances, Homeostasis, Humans, Platelet Adhesiveness, Platelet Activation, Immediate-Early Proteins, Platelet Glycoprotein GPIIb-IIIa Complex, Intercellular Signaling Peptides and Proteins, Mice, Connective Tissue Growth Factor, Cysteine-Rich Protein 61
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