Human 1 type IV collagen NC1 domain exhibits distinct antiangiogenic activity mediated by 1 1 integrin
Open accessAbstract
Human noncollagenous domain 1 of the alpha1 chain of type IV collagen [alpha1(IV)NC1], or arresten, is derived from the carboxy terminal of type IV collagen. It was shown to inhibit angiogenesis and tumor growth in vivo; however, the mechanisms involved are not known. In the present study we demonstrate that human alpha1(IV)NC1 binds to alpha1beta1 integrin, competes with type IV collagen binding to alpha1beta1 integrin, and inhibits migration, proliferation, and tube formation by ECs. Also, alpha1(IV)NC1 pretreatment inhibited FAK/c-Raf/MEK/ERK1/2/p38 MAPK activation in ECs but had no effect on the PI3K/Akt pathway. In contrast, alpha1(IV)NC1 did not affect proliferation, migration, or the activation of FAK/c-Raf/MEK1/2/p38/ERK1 MAPK pathway in alpha1 integrin receptor knockout ECs. Consistent with this, alpha1(IV)NC1 elicited significant antiangiogenic effects and tumor growth inhibition in vivo but failed to do the same in alpha1 integrin receptor knockout mice. This suggests a highly specific, alpha1beta1 integrin-dependent antiangiogenic activity of alpha1(IV)NC1. In addition, alpha1(IV)NC1 inhibited hypoxia-induced expression of hypoxia-inducible factor 1alpha and VEGF in ECs cultured on type IV collagen by inhibiting ERK1/2 and p38 activation. This unravels a hitherto unknown function of human alpha1(IV)NC1 and suggests a critical role for integrins in hypoxia and hypoxia-induced angiogenesis. Collectively, the above data indicate that alpha1(IV)NC1 is a potential therapeutic candidate for targeting tumor angiogenesis.
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The C-terminal non-collagenous (NC1) domain of collagen has been reported as an inhibitor of angiogenesis.
“The C-terminal non-collagenous (NC1) domain of the collagen has been reported as an inhibitor of angiogenesis (29–31).”
From Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration (2011) · cites this paper as [30]
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- Authors
- Sudhakar, A.
- Affiliations
- Creighton University (US)
- Corresponding author
- Sudhakar, A.
- Venue
- Journal of Clinical Investigation
- Published
- 2005-10-01
- Volume
- 115
- Issue
- 10
- Pages
- 2801-2810
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1199529
- OpenAlex
- W2130650067
- Cited by
- 162
- References
- 70
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2022: 5 · 2021: 3 · 2020: 7 · 2019: 5 · 2018: 6 · 2017: 3 · 2016: 9 · 2015: 9 · 2014: 11 · 2013: 10 · 2012: 12
- FWCI
- 5.29
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- retraction (2020-01-02)
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- Flight Attendant Medical Research Institute
- National Institutes of Health (DK 55001)
- National Cancer Institute (P30CA016672)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK55000, R01DK055000, DK 62987, R01DK062987, DK-55001, R01DK055001)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- alpha1beta1 integrin, antiangiogenic activity, tumor angiogenesis, endothelial cell migration, endothelial cell proliferation, tube formation, PI3K/Akt signaling, hypoxia, hypoxia-inducible factor-1α, vascular endothelial growth factor, tumor growth inhibition
- MeSH terms
- Enzyme Activation, Fetal Blood, Humans, Neoplasms, Neovascularization, Pathologic, Protein Kinases, Cell Hypoxia, Gene Deletion, Protein Structure, Tertiary, Angiogenesis Inhibitors, MAP Kinase Signaling System, Collagen Type IV, Integrin alpha1beta1, Vascular Endothelial Growth Factor A, Endothelial Cells, Hypoxia-Inducible Factor 1, alpha Subunit
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