CCN1 interlinks integrin and Hippo pathway to autoregulate tip cell activity

  1. Myo-Hyeon Park
  2. Ae Kyung Kim
  3. Sarala Manandhar
  4. Su-Young Oh
  5. Gun-Hyuk Jang
  6. Li Kang
  7. Dong-Won Lee
  8. Do Young Hyeon
  9. Sun-Hee Lee
  10. Hye Eun Lee
  11. Tae-Lin Huh
  12. Sang Heon Suh
  13. Daehee Hwang
  14. Kyunghee Byun
  15. Hae-Chul Park
  16. You Mie Lee  Is a corresponding author
  1. Kyungpook National University, Republic of Korea
  2. Korea University, Ansan Hospital, Republic of Korea
  3. POSTECH, Republic of Korea
  4. Chonnam National University Hospital, Republic of Korea
  5. Daegu Gyeongbuk Institute of Science and Technology, Republic of Korea
  6. Gachon University, Republic of Korea

Abstract

CCN1 (CYR61) stimulates active angiogenesis in various tumours, although the mechanism is largely unknown. Here, we report that CCN1 is a key regulator of endothelial tip cell activity in angiogenesis. Microvessel networks and directional vascular cell migration patterns were deformed in ccn1-knockdown zebrafish embryos. CCN1 activated VEGFR2 and downstream MAPK/PI3K signalling pathways, YAP/TAZ, as well as Rho effector mDia1 to enhance tip cell activity and CCN1 itself. VEGFR2 interacted with integrin αvβ3 through CCN1. Integrin αvβ3 inhibitor repressed tip cell number and sprouting in postnatal retinas from endothelial cell-specific Ccn1 transgenic mice, and allograft tumours in Ccn1 transgenic mice showed hyperactive vascular sprouting. Cancer patients with high CCN1 expression have poor survival outcomes and positive correlation with ITGAV and ITGB3 and high YAP/WWTR1. Thus, our data underscore the positive feedback regulation of tip cells by CCN1 through integrin αvβ3/VEGFR2 and increased YAP/TAZ activity, suggesting a promising therapeutic intervention for pathological angiogenesis.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files

Article and author information

Author details

  1. Myo-Hyeon Park

    College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  2. Ae Kyung Kim

    College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  3. Sarala Manandhar

    College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  4. Su-Young Oh

    College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  5. Gun-Hyuk Jang

    College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  6. Li Kang

    College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  7. Dong-Won Lee

    Department of Biomedical Sciences, Korea University, Ansan Hospital, Gyeonggi-do, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  8. Do Young Hyeon

    School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  9. Sun-Hee Lee

    College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  10. Hye Eun Lee

    College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  11. Tae-Lin Huh

    School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  12. Sang Heon Suh

    Department of Internal Medicine, Chonnam National University Hospital, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  13. Daehee Hwang

    Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  14. Kyunghee Byun

    School of Medicine, Gachon University, Incheon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  15. Hae-Chul Park

    Department of Biomedical Sciences, Korea University, Ansan Hospital, Gyeonggi-do, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  16. You Mie Lee

    Collage of Pharmacy, Kyungpook National University, Daegu, Republic of Korea
    For correspondence
    lym@knu.ac.kr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5756-7169

Funding

National Research Foundation of Korea (NRF-2013R1A2A2A01068868)

  • You Mie Lee

National Research Foundation of Korea (NRF-2017R1A2B3002227)

  • You Mie Lee

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Gou Young Koh, Institute of Basic Science and Korea Advanced Institute of Science and Technology (KAIST), Korea (South), Republic of

Ethics

Animal experimentation: The animal handling and experimental procedures were strictly conducted as per the Guidelines for Care and Use of Laboratory Animals issued by the Institutional Ethical Animal Care Committee of Kyungpook National University

Version history

  1. Received: February 12, 2019
  2. Accepted: August 15, 2019
  3. Accepted Manuscript published: August 20, 2019 (version 1)
  4. Version of Record published: September 4, 2019 (version 2)

Copyright

© 2019, Park et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Myo-Hyeon Park
  2. Ae Kyung Kim
  3. Sarala Manandhar
  4. Su-Young Oh
  5. Gun-Hyuk Jang
  6. Li Kang
  7. Dong-Won Lee
  8. Do Young Hyeon
  9. Sun-Hee Lee
  10. Hye Eun Lee
  11. Tae-Lin Huh
  12. Sang Heon Suh
  13. Daehee Hwang
  14. Kyunghee Byun
  15. Hae-Chul Park
  16. You Mie Lee
(2019)
CCN1 interlinks integrin and Hippo pathway to autoregulate tip cell activity
eLife 8:e46012.
https://doi.org/10.7554/eLife.46012

Share this article

https://doi.org/10.7554/eLife.46012

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