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Cited by 195Connective Tissue Growth Factor ResearchCell Adhesion Molecules ResearchProteoglycans and glycosaminoglycans research

Adhesion of Human Skin Fibroblasts to Cyr61 Is Mediated through Integrin α6β1 and Cell Surface Heparan Sulfate Proteoglycans

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Chen, Ningyu, Chen, Chih-Chiun, Lau, Lester F.·2000·Journal of Biological Chemistry
DOI 10.1074/jbc.m003040200
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Abstract

The angiogenic inducer Cyr61 is an extracellular matrix-associated heparin-binding protein that can mediate cell adhesion, stimulate cell migration, and enhance growth factor-stimulated DNA synthesis in both fibroblasts and endothelial cells in culture. In vivo, Cyr61 induces neovascularization and promotes tumor growth. Cyr61 is a prototypic member of a highly conserved family of secreted proteins that includes connective tissue growth factor, nephroblastoma overexpressed, Elm-1/WISP-1, Cop-1/WISP-2, and WISP-3. Encoded by an immediate early gene, Cyr61 synthesis is induced by serum growth factors in cultured fibroblasts and in dermal fibroblasts during cutaneous wound healing. We previously demonstrated that Cyr61 mediates adhesion of vascular endothelial cells and activation-dependent adhesion of blood platelets through direct interaction with integrins alpha(V)beta(3) and alpha(IIb)beta(3), respectively. In this study, we show that the adhesion of primary human skin fibroblasts to Cyr61 is mediated through integrin alpha(6)beta(1) and cell surface heparan sulfate proteoglycans (HSPGs), which most likely serve as co-receptors. Either destruction of cell surface HSPGs or prior occupancy of the Cyr61 heparin-binding site completely blocked cell adhesion to Cyr61. A heparin-binding defective mutant of Cyr61 was unable to mediate fibroblast adhesion through integrin alpha(6)beta(1) but still mediated endothelial cell adhesion through integrin alpha(V)beta(3), indicating that endothelial cell adhesion through integrin alpha(V)beta(3) is independent of the heparin-binding activity of Cyr61. These results identify Cyr61 as a novel adhesive substrate for integrin alpha(6)beta(1) and provide the first demonstration of the requirement for HSPGs in integrin-mediated cell attachment. In addition, these findings suggest that Cyr61 might elicit disparate biological effects in different cell types through interaction with distinct integrin receptors.

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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 [55]

  • CCN1 binds HSPGs with high affinity, which serve as co-receptors with integrins in some contexts; syndecan-4 is the critical HSPG for CCN1 functions where examined.

    “CCN1 binds HSPGs with high affinity, which serve as co-receptors with integrins in some contexts [13,55]. Where examined, syndecan-4 has been identified as the HSPG critical for CCN1 functions [61,62].”

    From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [55]

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Research works printed but not linked: 6

  1. Babic, A. M., Kireeva, M. L., Kolesnikova, T. V., and Lau, L. F. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 6355-6360
  2. Latinkic, B. V. (1994) Regulation of Expression of Growth Factor-inducible Immediate-Early Genes CyrG1 and PIP92. Ph.D. Thesis. The University of Illinois at Chicago 15. Gumbiner, B. M. (1996) Cell 84, 345-357
  3. Pigott, R., and Power, C. (1993) The Adhesion Molecule, pp. 158 -186, Academic Press, San Diego, CA 25.
  4. Saoncella, S., Echtermeyer, F., Denhez, F., Nowlen, J. K., Mosher, D. F., Robinson, S. D., Hynes, R. O., and Goetinck, P. F. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 2805-2810
  5. Myles, D. G., Kimmel, L. H., Blobel, C. P., White, J. M., and Primakoff, P. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 4195-4198
  6. Pennica, D., Swanson, T. A., Welsh, J. W., Roy, M. A., Lawrence, D. A., Lee, J., Brush, J., Taneyhill, L. A., Deuel, B., Lew, M., Watanabe, C., Cohen, R. L., Melhem, M. F., Finley, G. G., Quirke, P., Goddard, A. D., Hillan, K. J., Gurney, A. L., Botstein, D., and Levine, A. J. (1998) Proc. Natl. Acad. Sci.

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Authors
Chen, N., Chen, C.-C., & Lau, L. F.
Affiliations
University of Illinois Chicago (US)
Corresponding author
Lau, Lester F.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2000-08
Volume
275
Issue
32
Pages
24953-24961
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m003040200
OpenAlex
W2080144763
Cited by
195
References
55
Citations by year
2026: 3 · 2025: 6 · 2024: 6 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 8 · 2019: 6 · 2017: 3 · 2016: 6 · 2015: 9 · 2014: 4 · 2013: 8 · 2012: 5
FWCI
6.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (R01CA046565, CA-46565)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
Keywords
CYR61, alpha6beta1 integrin, heparan sulfate proteoglycans, cell adhesion, dermal fibroblasts, integrin αvβ3, endothelial cell adhesion, co-receptors, angiogenesis, wound healing
MeSH terms
Animals, Cell Adhesion, Cell Line, Cell Membrane, Fibroblasts, Glycosaminoglycans, Growth Substances, Humans, Kinetics, Male, Recombinant Proteins, Skin, Transfection, Integrins, Polymerase Chain Reaction, Mutagenesis, Site-Directed, Extracellular Matrix Proteins, Receptors, Fibronectin, Receptors, Laminin, Genes, Immediate-Early, Immediate-Early Proteins, Spodoptera, Receptors, Vitronectin, Heparan Sulfate Proteoglycans, Intercellular Signaling Peptides and Proteins, Integrin alpha6beta1, Mice, Cysteine-Rich Protein 61

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