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KRAS regulation by small non-coding RNAs and SNARE proteins

Author

Listed:
  • Yonglu Che

    (Stanford University
    Stanford University)

  • Zurab Siprashvili

    (Stanford University
    Stanford University)

  • Joanna R. Kovalski

    (Stanford University
    Stanford University)

  • Tiffany Jiang

    (Stanford University)

  • Glenn Wozniak

    (Stanford University)

  • Lara Elcavage

    (Stanford University)

  • Paul A. Khavari

    (Stanford University
    Stanford University
    VA Palo Alto Healthcare System)

Abstract

KRAS receives and relays signals at the plasma membrane (PM) where it transmits extracellular growth factor signals to downstream effectors. SNORD50A/B were recently found to bind KRAS and inhibit its tumorigenic action by unknown mechanisms. KRAS proximity protein labeling was therefore undertaken in SNORD50A/B wild-type and knockout cells, revealing that SNORD50A/B RNAs shape the composition of proteins proximal to KRAS, notably by inhibiting KRAS proximity to the SNARE vesicular transport proteins SNAP23, SNAP29, and VAMP3. To remain enriched on the PM, KRAS undergoes cycles of endocytosis, solubilization, and vesicular transport to the PM. Here we report that SNAREs are essential for the final step of this process, with KRAS localization to the PM facilitated by SNAREs but antagonized by SNORD50A/B. Antagonism between SNORD50A/B RNAs and specific SNARE proteins thus controls KRAS localization, signaling, and tumorigenesis, and disrupting SNARE-enabled KRAS function represents a potential therapeutic opportunity in KRAS-driven cancer.

Suggested Citation

  • Yonglu Che & Zurab Siprashvili & Joanna R. Kovalski & Tiffany Jiang & Glenn Wozniak & Lara Elcavage & Paul A. Khavari, 2019. "KRAS regulation by small non-coding RNAs and SNARE proteins," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13106-4
    DOI: 10.1038/s41467-019-13106-4
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