IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-45499-2.html
   My bibliography  Save this article

Molecular basis of VEGFR1 autoinhibition at the plasma membrane

Author

Listed:
  • Manas Pratim Chakraborty

    (Indian Institute of Science Education and Research Kolkata, Mohanpur campus)

  • Diptatanu Das

    (Indian Institute of Science Education and Research Kolkata, Mohanpur campus)

  • Purav Mondal

    (Indian Institute of Science Education and Research Kolkata, Mohanpur campus)

  • Pragya Kaul

    (Indian Institute of Science Education and Research Kolkata, Mohanpur campus)

  • Soumi Bhattacharyya

    (Indian Institute of Science Education and Research Kolkata, Mohanpur campus)

  • Prosad Kumar Das

    (Indian Institute of Science Education and Research Kolkata, Mohanpur campus)

  • Rahul Das

    (Indian Institute of Science Education and Research Kolkata, Mohanpur campus
    Indian Institute of Science Education and Research Kolkata, Mohanpur campus)

Abstract

Ligand-independent activation of VEGFRs is a hallmark of diabetes and several cancers. Like EGFR, VEGFR2 is activated spontaneously at high receptor concentrations. VEGFR1, on the other hand, remains constitutively inactive in the unligated state, making it an exception among VEGFRs. Ligand stimulation transiently phosphorylates VEGFR1 and induces weak kinase activation in endothelial cells. Recent studies, however, suggest that VEGFR1 signaling is indispensable in regulating various physiological or pathological events. The reason why VEGFR1 is regulated differently from other VEGFRs remains unknown. Here, we elucidate a mechanism of juxtamembrane inhibition that shifts the equilibrium of VEGFR1 towards the inactive state, rendering it an inefficient kinase. The juxtamembrane inhibition of VEGFR1 suppresses its basal phosphorylation even at high receptor concentrations and transiently stabilizes tyrosine phosphorylation after ligand stimulation. We conclude that a subtle imbalance in phosphatase activation or removing juxtamembrane inhibition is sufficient to induce ligand-independent activation of VEGFR1 and sustain tyrosine phosphorylation.

Suggested Citation

  • Manas Pratim Chakraborty & Diptatanu Das & Purav Mondal & Pragya Kaul & Soumi Bhattacharyya & Prosad Kumar Das & Rahul Das, 2024. "Molecular basis of VEGFR1 autoinhibition at the plasma membrane," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45499-2
    DOI: 10.1038/s41467-024-45499-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-45499-2
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-45499-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Sarvenaz Sarabipour & Kalina Hristova, 2016. "Mechanism of FGF receptor dimerization and activation," Nature Communications, Nature, vol. 7(1), pages 1-12, April.
    2. Inhee Chung & Robert Akita & Richard Vandlen & Derek Toomre & Joseph Schlessinger & Ira Mellman, 2010. "Spatial control of EGF receptor activation by reversible dimerization on living cells," Nature, Nature, vol. 464(7289), pages 783-787, April.
    3. Hanna M. Eilken & Rodrigo Diéguez-Hurtado & Inga Schmidt & Masanori Nakayama & Hyun-Woo Jeong & Hendrik Arf & Susanne Adams & Napoleone Ferrara & Ralf H. Adams, 2017. "Pericytes regulate VEGF-induced endothelial sprouting through VEGFR1," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    4. Dipankar Ash & Varadarajan Sudhahar & Seock-Won Youn & Mustafa Nazir Okur & Archita Das & John P. O’Bryan & Maggie McMenamin & Yali Hou & Jack H. Kaplan & Tohru Fukai & Masuko Ushio-Fukai, 2021. "The P-type ATPase transporter ATP7A promotes angiogenesis by limiting autophagic degradation of VEGFR2," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    5. Laura C. Zanetti-Domingues & Dimitrios Korovesis & Sarah R. Needham & Christopher J. Tynan & Shiori Sagawa & Selene K. Roberts & Antonija Kuzmanic & Elena Ortiz-Zapater & Purvi Jain & Rob C. Roovers &, 2018. "The architecture of EGFR’s basal complexes reveals autoinhibition mechanisms in dimers and oligomers," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Shwetha Srinivasan & Raju Regmi & Xingcheng Lin & Courtney A. Dreyer & Xuyan Chen & Steven D. Quinn & Wei He & Matthew A. Coleman & Kermit L. Carraway & Bin Zhang & Gabriela S. Schlau-Cohen, 2022. "Ligand-induced transmembrane conformational coupling in monomeric EGFR," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Michael G. Sugiyama & Aidan I. Brown & Jesus Vega-Lugo & Jazlyn P. Borges & Andrew M. Scott & Khuloud Jaqaman & Gregory D. Fairn & Costin N. Antonescu, 2023. "Confinement of unliganded EGFR by tetraspanin nanodomains gates EGFR ligand binding and signaling," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Ziya Kalay & Takahiro K Fujiwara & Akihiro Kusumi, 2012. "Confining Domains Lead to Reaction Bursts: Reaction Kinetics in the Plasma Membrane," PLOS ONE, Public Library of Science, vol. 7(3), pages 1-8, March.
    4. Zhdanov, Vladimir P., 2015. "Control of tissue growth by locally produced activator: Liver regeneration," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 421(C), pages 279-285.
    5. Hui Deng & Qian Lei & Chengdi Wang & Zhoufeng Wang & Hai Chen & Gang Wang & Na Yang & Dan Huang & Quanwei Yu & Mengling Yao & Xue Xiao & Guonian Zhu & Cheng Cheng & Yangqian Li & Feng Li & Panwen Tian, 2022. "A fluorogenic probe for predicting treatment response in non-small cell lung cancer with EGFR-activating mutations," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    6. Miroslav Blumenberg, 2014. "Differential Transcriptional Effects of EGFR Inhibitors," PLOS ONE, Public Library of Science, vol. 9(9), pages 1-14, September.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45499-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.