Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Human α1 type IV collagen NC1 domain exhibits distinct antiangiogenic activity mediated by α1β1 integrin
Akulapalli Sudhakar, … , Dominic Cosgrove, Raghu Kalluri
Akulapalli Sudhakar, … , Dominic Cosgrove, Raghu Kalluri
Published October 3, 2005
Citation Information: J Clin Invest. 2005;115(10):2801-2810. https://doi.org/10.1172/JCI24813.
View: Text | PDF | Retraction
Research Article Angiogenesis Article has an altmetric score of 10

Human α1 type IV collagen NC1 domain exhibits distinct antiangiogenic activity mediated by α1β1 integrin

  • Text
  • PDF
Abstract

Human noncollagenous domain 1 of the α1 chain of type IV collagen [α1(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 α1(IV)NC1 binds to α1β1 integrin, competes with type IV collagen binding to α1β1 integrin, and inhibits migration, proliferation, and tube formation by ECs. Also, α1(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, α1(IV)NC1 did not affect proliferation, migration, or the activation of FAK/c-Raf/MEK1/2/p38/ERK1 MAPK pathway in α1 integrin receptor knockout ECs. Consistent with this, α1(IV)NC1 elicited significant antiangiogenic effects and tumor growth inhibition in vivo but failed to do the same in α1 integrin receptor knockout mice. This suggests a highly specific, α1β1 integrin–dependent antiangiogenic activity of α1(IV)NC1. In addition, α1(IV)NC1 inhibited hypoxia-induced expression of hypoxia-inducible factor 1α and VEGF in ECs cultured on type IV collagen by inhibiting ERK1/2 and p38 activation. This unravels a hitherto unknown function of human α1(IV)NC1 and suggests a critical role for integrins in hypoxia and hypoxia-induced angiogenesis. Collectively, the above data indicate that α1(IV)NC1 is a potential therapeutic candidate for targeting tumor angiogenesis.

Authors

Akulapalli Sudhakar, Pia Nyberg, Venkateshwar G. Keshamouni, Arjuna P. Mannam, Jian Li, Hikaru Sugimoto, Dominic Cosgrove, Raghu Kalluri

×

Figure 2

Options: View larger image (or click on image) Download as PowerPoint
α1β1 integrin is a functional receptor for α1(IV)NC1. (A) Cell attachmen...
α1β1 integrin is a functional receptor for α1(IV)NC1. (A) Cell attachment assay. Attachment of overnight serum-starved HUVECs on α1(IV)NC1-coated plates was significantly inhibited (75.14%) by incubation with soluble α1β1 protein, whereas α5β1 or αVβ3 integrin had no significant effect. α1β1 integrin–induced cell attachment inhibition was reversed by addition of soluble α1(IV)NC1 protein to the culture media. (B) Cell adhesion assay. Serum-starved HUVEC attachment to type IV collagen–coated plates was significantly inhibited in the presence of soluble α1β1 integrin (61.7%), or α1(IV)NC1 protein (67.14%), whereas α5β1 or αVβ3 integrin had no significant effect. α1β1 integrin–induced cell attachment inhibition was reversed by addition of equimolar soluble α1(IV)NC1 protein to the HUVEC culture media. The graph summarizes the average results of 3 independent experiments. (C) Immunoprecipitation and immunoblot. HUVECs treated with α1(IV)NC1 for 45 minutes were lysed and immunoprecipitated with α1β1 (bottom panel). Western blot analysis of the precipitate for bound α1(IV)NC1 is shown (top panel). A specific band at 26 kDa was produced in a dose-dependent manner after 45 minutes of incubation with α1(IV)NC1 and was absent in lysate of untreated cells.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Blogged by 1
Referenced in 2 Wikipedia pages
Highlighted by 1 platforms
98 readers on Mendeley
See more details