IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v7y2016i1d10.1038_ncomms10647.html
   My bibliography  Save this article

KRAS insertion mutations are oncogenic and exhibit distinct functional properties

Author

Listed:
  • Yasmine White

    (University of California)

  • Aditi Bagchi

    (Department of Pediatrics, Division of Pediatric Hematology/Oncology and Bone Marrow Transplantation; Helen DeVos Children’s Hospital/Spectrum Health Medical Group
    Helen DeVos Children’s Hospital/Spectrum Health Medical Group
    Van Andel Institute Graduate School)

  • Jessica Van Ziffle

    (University of California)

  • Anagha Inguva

    (University of California)

  • Gideon Bollag

    (Plexxikon Inc)

  • Chao Zhang

    (Plexxikon Inc)

  • Heidi Carias

    (Plexxikon Inc)

  • David Dickens

    (Department of Pediatrics, Division of Pediatric Hematology/Oncology and Bone Marrow Transplantation; Helen DeVos Children’s Hospital/Spectrum Health Medical Group
    Helen DeVos Children’s Hospital/Spectrum Health Medical Group)

  • Mignon Loh

    (University of California
    Helen Diller Family Comprehensive Cancer Center, University of California)

  • Kevin Shannon

    (University of California
    Helen Diller Family Comprehensive Cancer Center, University of California)

  • Ari J. Firestone

    (University of California)

Abstract

Oncogenic KRAS mutations introduce discrete amino acid substitutions that reduce intrinsic Ras GTPase activity and confer resistance to GTPase-activating proteins (GAPs). Here we discover a partial duplication of the switch 2 domain of K-Ras encoding a tandem repeat of amino acids G60_A66dup in a child with an atypical myeloproliferative neoplasm. K-Ras proteins containing this tandem duplication or a similar five amino acid E62_A66dup mutation identified in lung and colon cancers transform the growth of primary myeloid progenitors and of Ba/F3 cells. Recombinant K-RasG60_A66dup and K-RasE62_A66dup proteins display reduced intrinsic GTP hydrolysis rates, accumulate in the GTP-bound conformation and are resistant to GAP-mediated GTP hydrolysis. Remarkably, K-Ras proteins with switch 2 insertions are impaired for PI3 kinase binding and Akt activation, and are hypersensitive to MEK inhibition. These studies illuminate a new class of oncogenic KRAS mutations and reveal unexpected plasticity in oncogenic Ras proteins that has diagnostic and therapeutic implications.

Suggested Citation

  • Yasmine White & Aditi Bagchi & Jessica Van Ziffle & Anagha Inguva & Gideon Bollag & Chao Zhang & Heidi Carias & David Dickens & Mignon Loh & Kevin Shannon & Ari J. Firestone, 2016. "KRAS insertion mutations are oncogenic and exhibit distinct functional properties," Nature Communications, Nature, vol. 7(1), pages 1-8, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10647
    DOI: 10.1038/ncomms10647
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms10647
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms10647?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
    ---><---

    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:7:y:2016:i:1:d:10.1038_ncomms10647. 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.

    We have no bibliographic references for this item. You can help adding them by using 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.