IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-27343-z.html
   My bibliography  Save this article

Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker

Author

Listed:
  • Bernhard C. Lechtenberg

    (Cancer Center, Sanford Burnham Prebys Medical Discovery Institute
    Ubiquitin Signalling Division, The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Marina P. Gehring

    (Cancer Center, Sanford Burnham Prebys Medical Discovery Institute)

  • Taylor P. Light

    (Johns Hopkins University)

  • Christopher R. Horne

    (Ubiquitin Signalling Division, The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Mike W. Matsumoto

    (Cancer Center, Sanford Burnham Prebys Medical Discovery Institute)

  • Kalina Hristova

    (Johns Hopkins University)

  • Elena B. Pasquale

    (Cancer Center, Sanford Burnham Prebys Medical Discovery Institute)

Abstract

Eph receptor tyrosine kinases play a key role in cell-cell communication. Lack of structural information on the entire multi-domain intracellular region of any Eph receptor has hindered understanding of their signaling mechanisms. Here, we use integrative structural biology to investigate the structure and dynamics of the EphA2 intracellular region. EphA2 promotes cancer malignancy through a poorly understood non-canonical form of signaling involving serine/threonine phosphorylation of the linker connecting its kinase and SAM domains. We show that accumulation of multiple linker negative charges, mimicking phosphorylation, induces cooperative changes in the EphA2 intracellular region from more closed to more extended conformations and perturbs the EphA2 juxtamembrane segment and kinase domain. In cells, linker negative charges promote EphA2 oligomerization. We also identify multiple kinases catalyzing linker phosphorylation. Our findings suggest multiple effects of linker phosphorylation on EphA2 signaling and imply that coordination of different kinases is necessary to promote EphA2 non-canonical signaling.

Suggested Citation

  • Bernhard C. Lechtenberg & Marina P. Gehring & Taylor P. Light & Christopher R. Horne & Mike W. Matsumoto & Kalina Hristova & Elena B. Pasquale, 2021. "Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27343-z
    DOI: 10.1038/s41467-021-27343-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-27343-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-27343-z?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. Yue Zhou & Naoki Yamada & Tomohiro Tanaka & Takashi Hori & Satoru Yokoyama & Yoshihiro Hayakawa & Seiji Yano & Junya Fukuoka & Keiichi Koizumi & Ikuo Saiki & Hiroaki Sakurai, 2015. "Crucial roles of RSK in cell motility by catalysing serine phosphorylation of EphA2," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    2. Rosalia Fernandez-Alonso & Francisco Bustos & Manon Budzyk & Pankaj Kumar & Andreas O. Helbig & Jens Hukelmann & Angus I. Lamond & Fredrik Lanner & Houjiang Zhou & Evangelia Petsalaki & Greg M. Findla, 2020. "Phosphoproteomics identifies a bimodal EPHA2 receptor switch that promotes embryonic stem cell differentiation," Nature Communications, Nature, vol. 11(1), pages 1-13, 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. Sergi Marco & Matthew Neilson & Madeleine Moore & Arantxa Perez-Garcia & Holly Hall & Louise Mitchell & Sergio Lilla & Giovani R. Blanco & Ann Hedley & Sara Zanivan & Jim C. Norman, 2021. "Nuclear-capture of endosomes depletes nuclear G-actin to promote SRF/MRTF activation and cancer cell invasion," Nature Communications, Nature, vol. 12(1), pages 1-19, December.

    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:12:y:2021:i:1:d:10.1038_s41467-021-27343-z. 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.